The Safe Path at the Fork: Ensuring Replication-Associated DNA Double-Strand Breaks are Repaired by Homologous Recombination DOI Creative Commons
Jac A. Nickoloff, Neelam Sharma, Lynn Taylor

et al.

Frontiers in Genetics, Journal Year: 2021, Volume and Issue: 12

Published: Sept. 27, 2021

Cells must replicate and segregate their DNA to daughter cells accurately maintain genome stability prevent cancer. replication is usually fast accurate, with intrinsic (proofreading) extrinsic (mismatch repair) error-correction systems. However, forks slow or stop when they encounter lesions, natural pause sites, difficult-to-replicate sequences, are treated polymerase inhibitors hydroxyurea, which depletes nucleotide pools. These challenges termed stress, respond by activating damage response signaling pathways that delay cell cycle progression, stimulate repair fork restart, induce apoptosis. Stressed managed rescue from adjacent forks, repriming, translesion synthesis, template switching, reversal produces a single-ended double-strand break (seDSB). also collapse seDSBs single-strand nicks cleaved structure-specific nucleases. Reversed can be restarted homologous recombination (HR), but pose risks of mis-rejoining non-homologous end-joining (NHEJ) other DSBs, causing rearrangements. HR requires resection broken ends create 3’ single-stranded for RAD51 recombinase loading, resected refractory NHEJ. This Mini Review highlights mechanisms help promoting accurate restart HR.

Language: Английский

Targeting replication stress in cancer therapy DOI
Alexandre André Balieiro Anastácio da Costa, Dipanjan Chowdhury, Geoffrey I. Shapiro

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 22(1), P. 38 - 58

Published: Oct. 6, 2022

Language: Английский

Citations

193
Metabolic regulation of homologous recombination repair by MRE11 lactylation DOI Creative Commons
Yuping Chen, Jinhuan Wu, Linhui Zhai

et al.

Cell, Journal Year: 2023, Volume and Issue: 187(2), P. 294 - 311.e21

Published: Dec. 20, 2023

Language: Английский

Citations

134
Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells DOI Creative Commons

Stephanie Tirman,

Annabel Quinet, Matthew Wood

et al.

Molecular Cell, Journal Year: 2021, Volume and Issue: 81(19), P. 4026 - 4040.e8

Published: Oct. 1, 2021

Language: Английский

Citations

130
Leveraging the replication stress response to optimize cancer therapy DOI
Emily Cybulla, Alessandro Vindigni

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 23(1), P. 6 - 24

Published: Nov. 2, 2022

Language: Английский

Citations

70
Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy DOI Creative Commons
Jay Ramanlal Anand, Lilly Chiou,

Carly A. Sciandra

et al.

NAR Cancer, Journal Year: 2023, Volume and Issue: 5(1)

Published: Jan. 11, 2023

Abstract DNA damage tolerance and mutagenesis are hallmarks enabling characteristics of neoplastic cells that drive tumorigenesis allow cancer to resist therapy. The ‘Y-family’ trans-lesion synthesis (TLS) polymerases enable replicate damaged genomes, thereby conferring tolerance. Moreover, Y-family inherently error-prone cause mutations. Therefore, TLS potential mediators important tumorigenic phenotypes. skin cancer-propensity syndrome xeroderma pigmentosum-variant (XPV) results from defects in the Polymerase Pol eta (Polη) compensatory deployment alternative inappropriate polymerases. However, extent which dysregulated contributes underlying etiology other human cancers is unclear. Here we consider broad impact on We survey ways pathologically altered cancer. summarize evidence shape review studies implicating as a driver carcinogenesis. Because many treatment regimens comprise DNA-damaging agents, pharmacological inhibition an attractive strategy for sensitizing tumors genotoxic therapies. discuss tractability pathway recent progress development inhibitors therapeutic purposes.

Language: Английский

Citations

45
APOBEC3A induces DNA gaps through PRIMPOL and confers gap-associated therapeutic vulnerability DOI Creative Commons
Ajinkya S. Kawale, Xiaojuan Ran, Parasvi S. Patel

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(3)

Published: Jan. 19, 2024

Mutation signatures associated with apolipoprotein B mRNA editing catalytic polypeptide-like 3A/B (APOBEC3A/B) cytidine deaminases are prevalent across cancers, implying their roles as mutagenic drivers during tumorigenesis and tumor evolution. APOBEC3A (A3A) expression induces DNA replication stress increases the cellular dependency on ataxia telangiectasia Rad3-related (ATR) kinase for survival. Nonetheless, how A3A remains unclear. We show that without slowing forks. find single-stranded (ssDNA) gaps through PrimPol-mediated repriming. A3A-induced ssDNA repaired by multiple pathways involving ATR, RAD51, translesion synthesis. Both ATR inhibition trapping of poly(ADP-ribose) polymerase (PARP) PARP inhibitor impair repair gaps, preferentially killing A3A-expressing cells. When used in combination, inhibitors selectively kill cells synergistically a manner dependent PrimPol-generated gaps. Thus, arises from which confer therapeutic vulnerability to gap-targeted inhibitors.

Language: Английский

Citations

18
Transcription–Replication Conflicts as a Source of Genome Instability DOI Creative Commons

Liana Goehring,

Tony T. Huang, Duncan J. Smith

et al.

Annual Review of Genetics, Journal Year: 2023, Volume and Issue: 57(1), P. 157 - 179

Published: Aug. 8, 2023

Transcription and replication both require large macromolecular complexes to act on a DNA template, yet these machineries cannot simultaneously the same sequence. Conflicts between transcription (transcription–replication conflicts, or TRCs) are widespread in prokaryotes eukaryotes have capacity cause damage compromise complete, faithful of genome. This review will highlight recent studies investigating genomic locations TRCs mechanisms by which they may be prevented, mitigated, resolved. We address work from model organisms mammalian systems but predominantly focus multicellular owing additional complexities inherent coordination context cell type–specific gene expression higher-order chromatin organization.

Language: Английский

Citations

33
Emerging strategies for cancer therapy by ATR inhibitors DOI Creative Commons

Kimiyoshi Yano,

Bunsyo Shiotani

Cancer Science, Journal Year: 2023, Volume and Issue: 114(7), P. 2709 - 2721

Published: May 15, 2023

DNA replication stress (RS) causes genomic instability and vulnerability in cancer cells. To counteract RS, cells have evolved various mechanisms involving the ATR kinase signaling pathway, which regulates origin firing, cell cycle checkpoints, fork stabilization to secure fidelity of replication. However, also alleviates RS support survival by driving tolerance, thereby contributing therapeutic resistance. Cancer harboring genetic mutations other changes that disrupt normal increase risk damage levels conferring addiction activity for sustainable susceptibility approaches using inhibitors (ATRis). Therefore, clinical trials are currently being conducted evaluate efficacy ATRis as monotherapies or combination with drugs biomarkers. In this review, we discuss recent advances elucidation functions response its relevance when utilizing ATRis.

Language: Английский

Citations

29
USP1-dependent nucleolytic expansion of PRIMPOL-generated nascent DNA strand discontinuities during replication stress DOI Creative Commons
Alexandra Nusawardhana,

Lindsey M Pale,

Claudia M. Nicolae

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(5), P. 2340 - 2354

Published: Jan. 5, 2024

DNA replication stress-induced fork arrest represents a significant threat to genomic integrity. One major mechanism of restart involves repriming downstream the arrested by PRIMPOL, leaving behind single-stranded (ssDNA) gap. Accumulation nascent strand ssDNA gaps has emerged as possible determinant cellular hypersensitivity genotoxic agents in certain genetic backgrounds such BRCA deficiency, but how are converted into cytotoxic structures is still unclear. Here, we investigate processing PRIMPOL-dependent upon stress induced hydroxyurea and cisplatin. We show that generated PRIMPOL-overexpressing cells expanded 3'-5' direction MRE11 exonuclease, 5'-3' EXO1 exonuclease. This bidirectional exonucleolytic gap expansion ultimately promotes their conversion DSBs. moreover identify de-ubiquitinating enzyme USP1 critical regulator PRIMPOL-generated gaps. accumulation during S-phase, nucleases. activity linked its role PCNA, suggesting PCNA ubiquitination prevents replication. Finally, depletion suppresses DSB formation cells, highlighting an unexpected for promoting instability under these conditions.

Language: Английский

Citations

13
Revisiting the BRCA-pathway through the lens of replication gap suppression DOI
Sharon B. Cantor

DNA repair, Journal Year: 2021, Volume and Issue: 107, P. 103209 - 103209

Published: Aug. 13, 2021

Language: Английский

Citations

46