Biomolecular condensates at sites of DNA damage: More than just a phase DOI Creative Commons

Vincent Spegg,

Matthias Altmeyer

DNA repair, Journal Year: 2021, Volume and Issue: 106, P. 103179 - 103179

Published: July 14, 2021

Protein recruitment to DNA break sites is an integral part of the damage response (DDR). Elucidation hierarchy and temporal order with which sensors as well repair signaling factors assemble around chromosome breaks has painted a complex picture tightly regulated macromolecular interactions that build specialized compartments facilitate maintenance genome integrity. While many underlying interactions, e.g. between damage-induced histone marks, can be explained by lock-and-key or induced fit binding models assuming fixed stoichiometries, structurally less defined such highly dynamic multivalent implicated in phase separation, also participate formation multi-protein assemblies genotoxic stress. Although much remains learned about these types cooperative their functional roles, rapidly growing interest material properties biomolecular condensates concepts from polymer chemistry soft matter physics understand biological processes at different scales holds great promises. Here, we discuss nuclear context integrity maintenance, highlighting potential clustered stoichiometric separation. Rather than viewing them opposing scenarios, combined effects balance structural specificity favorable physicochemical relevant for regulation function multilayered condensates.

Language: Английский

Histone post-translational modifications — cause and consequence of genome function DOI
Gonzalo Millán-Zambrano,

Adam Burton,

Andrew J. Bannister

et al.

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(9), P. 563 - 580

Published: March 25, 2022

Language: Английский

Citations

625
Targeting DNA damage response pathways in cancer DOI
Florian J. Groelly,

Matthew Fawkes,

Rebecca A. Dagg

et al.

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 23(2), P. 78 - 94

Published: Dec. 5, 2022

Language: Английский

Citations

461
PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells DOI Creative Commons
Sylvie M. Noordermeer, Haico van Attikum

Trends in Cell Biology, Journal Year: 2019, Volume and Issue: 29(10), P. 820 - 834

Published: Aug. 14, 2019

Homologous recombination (HR)-deficient tumors are hypersensitive to poly-(ADP)-ribose polymerase inhibitors (PARPi)-induced DNA damage. Therefore, PARPi have shown great promise in the clinic, but rates of pre-existing and acquired resistance high.Four main mechanisms been characterized, representing those that impact on (i) cellular availability inhibitor, (ii) activity abundance PAR chains, (iii) reactivation HR, (iv) replication fork protection.Loss 53BP1–RIF1–REV7–Shieldin axis, is involved non-homologous end-joining repair double-strand breaks, reactivates resection HR BRCA1-deficient cells, leading resistance. Shieldin seems shield broken ends by blocking access nucleases. The exact mechanism which controls needs be resolved.Studies large patient cohorts will need clarify clinical relevance different mechanisms. Furthermore, research drive future genetic screening factors guide therapy decisions. Poly-(ADP)-ribose (PARP) inhibition synthetic lethal with deficiency for homologous (HR), a pathway essential break repair. PARP (PARPi) therefore hold treatment disruptive mutations BRCA1/2 or other factors. Unfortunately, has proved major problem clinic. Knowledge about expanding quickly, revealing four alter drug availability, affect (de)PARylation enzymes, restore stability. We discuss how studies yielded important insights into regulation (DSB) protection, these could pave way novel options target vulnerabilities. Genomic instability one enabling characteristics tumor development [1.Hanahan D. Weinberg R.A. Hallmarks cancer: next generation.Cell. 2011; 144: 646-674Abstract Full Text PDF PubMed Scopus (24860) Google Scholar]. To maintain genomic integrity, cells equipped multiple wide variety lesions caused exogenous endogenous events. One particularly toxic lesion (DSB; see Glossary). This can ionizing irradiation genotoxic chemicals, also arise as an intermediate resolving stalled collapsed forks (replication instability) [2.Ait Saada A. et al.Preserving integrity competence via pathway.DNA Repair (Amst). 2018; 71: 135-147Crossref (0) If left unrepaired repaired incorrectly, DSBs give rise mutations, deletions, amplifications, chromosomal translocations, various outcomes such senescence, cell death, malignant transformation. Over 30 years ago, Marie-Claire King colleagues discovered linkage between familial early-onset breast cancer region 17q21 [3.Hall J.M. al.Linkage chromosome 17q21.Science. 1990; 250: 1684-1689Crossref now know gene affected BRCA1, this not only linked cases ovarian sporadic origins [4.Kandoth C. al.Mutational landscape significance across 12 types.Nature. 2013; 502: 333-339Crossref (1721) Scholar, 5.Martincorena I. Campbell P.J. Somatic mutation normal cells.Science. 2015; 349: 1483-1489Crossref (255) 6.Konstantinopoulos P.A. al.Homologous deficiency: exploiting fundamental vulnerability cancer.Cancer Discov. 5: 1137-1154Crossref (169) 7.Turner N.C. Signatures DNA-repair deficiencies cancer.N. Engl. J. Med. 2017; 377: 2490-2492Crossref (4) BRCA1 factor (HR) (see Box 1 more detailed overview DSB repair). Moreover, homozygous loss tolerated during human mouse embryonic [8.Evers B. Jonkers Mouse models BRCA2 past lessons, current understanding prospects.Oncogene. 2006; 25: 5885-5897Crossref (138) survival-dependency partially overcome concomitant p53 [9.Hakem R. al.Partial rescue Brca1 (5–6) early lethality p21 null mutation.Nat. Genet. 1997; 16: 298-302Crossref Importantly, mammary gland-specific genes show increased formation Indeed, samples, often co-occur – always TP53 10.Kringen P. al.TP53 carcinomas from carriers two distinct founder mutations; relation age at diagnosis survival.BMC Cancer. 2005; 134Crossref (16) Epigenetic silencing expression promoter hypermethylation another reducing activity, occur frequently [6.Konstantinopoulos 11.Shakeri H. al.Methylation analysis APC its relationship clinicopathological features.Clin. Lab. 2016; 62: 2333-2337Crossref (5) 12.Vos S. al.BRCA methylation versus BRCA germline mutation-related cancers.Breast Cancer Res. 19: 64Crossref In addition aberrations encoding many BRCA2, PALB2, RAD51, known tumors. All display severe result deregulated phenotype referred 'BRCAness' [13.Lord C.J. Ashworth BRCAness revisited.Nat. Rev. 110-120Crossref (287) Scholar].Box 1DNA Double-Strand Break RepairDSBs most cytotoxic because they cause full disruption chromosome. lead insertions, duplications, translocations. Cells (Figure I): canonical NHEJ (cNHEJ), alternative end joining (a-EJ), single-strand annealing (SSA).In mammalian cNHEJ frequent type [108.Mladenov E. Iliakis G. Induction double strand breaks: increasing spectrum pathways.Mutat. 711: 61-72Crossref (247) bound KU70/80 DNA-dependent protein kinase catalytic subunit (DNA-PKcs), forming DNA-PK complex, recruits ligation machinery XRCC4, ligase IV, XLF. requires no minimal end-processing, potentially small insertions deletions. plays role immune receptor diversification both V(D)J class-switch (CSR) mediated cNHEJ. core mentioned above, 53BP1 downstream RIF1, REV7, complex required efficient 2 information).In S G2, when occurs sister chromatid present, I). Upon extensive end-resection endo- exonucleases MRE11, CtIP, DNA2, EXO1, yielding 3′ single-stranded (ss)DNA overhangs, ssDNA stretch forms filaments RPA. Subsequently, RPA replaced RAD51 help BRCA2–PALB2 [109.Yuan S.S. al.BRCA2 radiation-induced assembly Rad51 vivo.Cancer 1999; 59: 3547-3551PubMed invades sequence present uses it template synthesis accurate several functions ranging activating enhancing recombinase [54.Bunting S.F. al.53BP1 inhibits Brca1-deficient breaks.Cell. 2010; 141: 243-254Abstract (810) 55.Bouwman rescues associated triple-negative BRCA-mutated cancers.Nat. Struct. Mol. Biol. 17: 688-695Crossref (520) 110.Zhao W. al.BRCA1–BARD1 promotes RAD51-mediated pairing.Nature. 550: 360-365Crossref Scholar].When compromised unavailable, employs error-prone a-EJ SSA some extent resection, characterized use microhomology [111.Roerink al.Polymerase theta-mediated replication-associated breaks elegans.Genome 2014; 24: 954-962Crossref (58) Scholar], dependent LIG3 POLQ. Loss deficiency, suggesting backup [112.Ceccaldi al.Homologous-recombination-deficient tumours Poltheta-mediated repair.Nature. 518: 258-262Crossref (213) 113.Mateos-Gomez al.Mammalian theta suppresses recombination.Nature. 254-257Crossref (190) larger stretches ERCC1 RAD52 [114.Bhargava al.Regulation genome maintenance.Trends 32: 566-575Abstract (62) Scholar] I).DSB choice tightly regulated throughout cycle restrict S/G2 phase. A CDK-specific phosphorylation event T847 CtIP enables cell-cycle phases [115.Huertas Jackson S.P. Human mediates control repair.J. Chem. 2009; 284: 9558-9565Crossref (259) addition, recruitment [57.Escribano-Diaz al.A cycle-dependent regulatory circuit composed 53BP1–RIF1 BRCA1–CtIP choice.Mol. Cell. 49: 872-883Abstract 63.Feng L. al.RIF1 counteracts BRCA1-mediated 288: 11135-11143Crossref (147) well interaction PALB2 [116.Orthwein suppression G1 cells.Nature. 528: 422-426Crossref necessary inhibited G1. S/G2-specific binding partner BARD1 unmethylated H4K20 new histones post-replicative chromatin [117.Nakamura K. al.H4K20me0 recognition BRCA1–BARD1 directs chromatids.Nat. Cell 2019; 21: 311-318Crossref association phase-specific exclude RIF1 association, thereby preventing [118.Chapman J.R. al.BRCA1-associated exclusion damage sites underlies temporal Sci. 2012; 125: 3529-3534Crossref (141) 119.Densham R.M. al.Human ubiquitin barriers resection.Nat. 23: 647-655Crossref Another inhibit KU-binding cyren, protecting overhangs [120.Arnoult N. G2 inhibitor CYREN.Nature. 549: 548-552Crossref (9) ensure activation takes place available. Remarkably, that, even 15–20% [121.Beucher al.ATM Artemis promote G2.EMBO 28: 3413-3427Crossref (291) indicates cycle-independent aspects may play choice, context complexity [122.Shibata al.Factors determining phase.EMBO 30: 1079-1092Crossref (256) (SSA). information). When HR-deficient renders highly sensitive damaging drugs platinum compounds, standard care decades. 2005, Bryant al. Farmer first described promising approach targeted BRCA1/2-deficient [14.Bryant H.E. al.Specific killing BRCA2-deficient poly(ADP-ribose) polymerase.Nature. 434: 913-917Crossref (2450) 15.Farmer al.Targeting defect mutant therapeutic strategy.Nature. 917-921Crossref (3206) family proteins post-translational PARylation substrate processes transcription PARP1 sensing (SSBs), recent data unligated Okazaki fragments trigger unperturbed S-phase [16.Hanzlikova al.The importance sensor replication.Mol. 71 (e313): 319-331Abstract block trap damaged 1). Such structures add effect posing insurmountable replisome [17.Murai al.Trapping PARP2 inhibitors.Cancer 72: 5588-5599Crossref (622) 18.Murai al.Stereospecific trapping BMN 673 comparison olaparib rucaparib.Mol. Ther. 13: 433-443Crossref (232) require functional resolve blocks resume progression, hence induce death trials explore using platinum-sensitive BRCA1/2-mutated showed [19.Fong P.C. al.Inhibition carriers.N. 361: 123-134Crossref (2335) 20.Mirza M.R. al.Latest evidence further cancer.Ann. Oncol. 29: 1366-1376Crossref Since 2014, FDA- and/or EMA-approved monotherapy combination (reviewed [21.Gourley al.Moving targeting response therapy.J. Clin. (Published online 13 May 2019. http://doi.org/10.1200/JCO.18.02050)Crossref Scholar]). Recently, Phase Ib trial encouraging results simultaneous chemical genetically proficient [22.Konstantinopoulos al.Olaparib alpha-specific PI3K alpelisib patients epithelial dose-escalation dose-expansion phase 1b trial.Lancet 20: 570-580Abstract chemically induced approaches open possibility treating types either deficient HR. Studies marred high 23.Rottenberg al.High sensitivity AZD2281 alone drugs.Proc. Natl. Acad. U. 2008; 105: 17079-17084Crossref (548) platinum-based chemotherapies strong predictor resistance, indicating probably share common [24.Fong al.Poly(ADP-ribose) inhibition: durable responses carrier correlating platinum-free interval.J. 2512-2519Crossref As vivo vitro studies, identified. These classified categories influence directly protection 2). review we knowledge improved our murine model tumors, majority displayed overexpression drug-efflux transporter (Abcb1a Abcb1b MDR1/P-gp, Abcg2) [23.Rottenberg mesenchymal carcinosarcomas epithelial-to-mesenchymal transition phenotypes especially accompanied Abcb1a/b [25.Jaspers J.E. al.BRCA2-deficient sarcomatoid exhibit multidrug resistance.Cancer 75: 732-741Crossref (18) was found topoisomerase I II (topotecan doxorubicin, respectively) 26.Rottenberg al.Selective induction chemotherapy conditional hereditary cancer.Proc. 2007; 104: 12117-12122Crossref Consequently, coadministration MDR1 tariquidar resensitized Overexpression ABCB1 observed PARPi-resistant line, reversed cotreatment verapamil elacridar [27.Vaidyanathan al.ABCB1 (MDR1) defines paclitaxel- olaparib-resistant cells.Br. 115: 431-441Crossref suggests upregulated chemotherapy-treated cancers translocations involving [28.Christie E.L. al.Multiple transcriptional fusions resistant high-grade serous cancer.Nat. Commun. 10: 1295Crossref

Language: Английский

Citations

377
The plasticity of DNA replication forks in response to clinically relevant genotoxic stress DOI

Matteo Berti,

David Cortez, Massimo Lopes

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 21(10), P. 633 - 651

Published: July 1, 2020

Language: Английский

Citations

279
The antitumorigenic roles of BRCA1–BARD1 in DNA repair and replication DOI
Madalena Tarsounas, Patrick Sung

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 21(5), P. 284 - 299

Published: Feb. 24, 2020

Language: Английский

Citations

278
Chromatin replication and epigenetic cell memory DOI
Kathleen R. Stewart-Morgan, Nataliya Petryk, Anja Groth

et al.

Nature Cell Biology, Journal Year: 2020, Volume and Issue: 22(4), P. 361 - 371

Published: March 30, 2020

Language: Английский

Citations

240
53BP1: a DSB escort DOI Open Access
Zachary Mirman, Titia de Lange

Genes & Development, Journal Year: 2020, Volume and Issue: 34(1-2), P. 7 - 23

Published: Jan. 1, 2020

53BP1 is an enigmatic DNA damage response factor that gained prominence because it determines the efficacy of PARP1 inhibitory drugs (PARPi) in BRCA1-deficient cancers. Recent studies have elevated from its modest status (yet another) to master regulator double-strand break (DSB) repair pathway choice. Our review literature suggests alternative view. We propose has evolved avoid mutagenic outcomes and does so by controlling processing ends dynamics DSBs. The consequences deficiency, such as diminished PARPi cells altered damaged telomeres, can be explained this viewpoint. further some fidelity functions coevolved with class switch recombination (CSR) immune system. speculate that, rather than being deterministic DSB choice, a escort guards against illegitimate potentially tumorigenic recombination.

Language: Английский

Citations

212
DNA End Resection: Mechanism and Control DOI
Petr Ćejka, Lorraine S. Symington

Annual Review of Genetics, Journal Year: 2021, Volume and Issue: 55(1), P. 285 - 307

Published: Nov. 23, 2021

DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genome integrity and cell viability. Typically, cells repair DSBs by either nonhomologous end joining (NHEJ) or homologous recombination (HR). The relative use of these two pathways depends on many factors, including cycle stage the nature ends. A critical determinant pathway selection is initiation 5′→3′ nucleolytic degradation ends, a process referred to as resection. End resection essential create single-stranded overhangs, which serve substrate for Rad51 recombinase initiate HR refractory NHEJ repair. Here, we review recent insights into mechanisms resection, how it regulated, pathological consequences its dysregulation.

Language: Английский

Citations

210
Histone Ubiquitination: An Integrative Signaling Platform in Genome Stability DOI Creative Commons
Francesca Mattiroli, Lorenza Penengo

Trends in Genetics, Journal Year: 2021, Volume and Issue: 37(6), P. 566 - 581

Published: Jan. 20, 2021

Complex mechanisms are in place to maintain genome stability. Ubiquitination of chromatin plays a central role these mechanisms. The ever-growing complexity the ubiquitin (Ub) code and modifications dynamics challenges our ability fully understand how histone ubiquitination regulates Here we review current knowledge on specific, low-abundant events that highly regulated within cellular DNA damage response (DDR), with particular emphasis latest discovery Ub phosphorylation as novel regulator DDR signaling pathway. We discuss players involved potential implications (phospho)ubiquitination structure, highlight exciting open questions for future research.

Language: Английский

Citations

160
BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination DOI
Jordan R. Becker,

Gillian Clifford,

Clara Bonnet

et al.

Nature, Journal Year: 2021, Volume and Issue: 596(7872), P. 433 - 437

Published: July 28, 2021

Language: Английский

Citations

141