What AlphaFold tells us about cohesin’s retention on and release from chromosomes DOI Open Access
Kim Nasmyth, Byung‐Gil Lee, Maurici B. Roig

et al.

Published: Oct. 23, 2023

Cohesin is a trimeric complex containing pair of SMC proteins (Smc1 and Smc3) whose ATPase domains at the end long coiled coils (CC) are interconnected by Scc1. During interphase, it organizes chromosomal DNA topology extruding loops in manner dependent on Scc1’s association with two large hook shaped called SA (yeast: Scc3) Nipbl (Scc2). The latter’s replacement Pds5 recruits Wapl, which induces release from chromatin via process requiring dissociation N-terminal domain (NTD) Smc3. If blocked Esco (Eco)-mediated Smc3 acetylation, cohesin merely maintains pre-existing loops, but third fate occurs during replication, when Pds5-containing associates Sororin forms structures that hold sister DNAs together. How Wapl blocks has hitherto remained mysterious. In twenty years since their discovery, not single testable hypothesis been proposed as to role. Here, AlphaFold 2 (AF) three-dimensional protein structure predictions lead us propose formation quarternary between SA, Pds5, NTD, latter juxtaposed (and subsequently sequestered by) highly conserved cleft within Wapl’s C-terminal (CTD). AF also reveals how arises distortion Smc3’s CC induced engagement domains, acetyl transferases recruited prevents binding Smc3/Scc1 interface. Our hypotheses explain phenotypes numerous existing mutations testable.

Language: Английский

Genome control by SMC complexes DOI
Claire Hoencamp, Benjamin D. Rowland

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(9), P. 633 - 650

Published: May 25, 2023

Language: Английский

Citations

65
NIPBL and cohesin: new take on a classic tale DOI Creative Commons
Dácil Alonso Gil, Ana Losada

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 33(10), P. 860 - 871

Published: April 15, 2023

Cohesin folds the genome in dynamic chromatin loops and holds sister chromatids together. NIPBLScc2 is currently considered cohesin loader, a role that may need reevaluation. NIPBL activates ATPase, which required for topological entrapment of DNAs to fuel DNA loop extrusion, but not association. Mechanistic dissection these processes suggests both STAG subunit bind DNA. also regulates conformational switches complex. Interactions with factors, including remodelers, replication proteins, transcriptional machinery, affect loading distribution. Here, we discuss recent research addressing how modulates activities its mutation causes developmental disorder, Cornelia de Lange Syndrome (CdLS).

Language: Английский

Citations

28
An extrinsic motor directs chromatin loop formation by cohesin DOI Creative Commons
Thomas M Guérin, Christopher Barrington, Georgii Pobegalov

et al.

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(19), P. 4173 - 4196

Published: Aug. 19, 2024

Language: Английский

Citations

9
A unified model for cohesin function in sisterchromatid cohesion and chromatin loop formation DOI Creative Commons
Frank Uhlmann

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(6), P. 1058 - 1071

Published: March 1, 2025

The ring-shaped cohesin complex topologically entraps two DNAs to establish sister chromatid cohesion. Cohesin also shapes the interphase chromatin landscape by forming DNA loops, which it is thought achieve using an in vitro-observed loop extrusion mechanism. However, recent studies revealed that loop-extrusion-deficient retains its ability form suggesting a divergence of vitro and vivo formation. Instead extrusion, we examine whether forms loops mechanism akin cohesion establishment: sequential topological capture DNAs. We explore similarities differences between "loop capture" extrusion" model, how they compare at explaining experimental observations, future approaches can delineate their possible respective contributions. extend our DNA-DNA model for function related structural maintenance chromosomes (SMC) family members, condensin, Smc5-Smc6 complex, bacterial SMC complexes.

Language: Английский

Citations

1
Cryo-EM reveals a nearly complete PCNA loading process and unique features of the human alternative clamp loader CTF18-RFC DOI Creative Commons
Qing He, Feng Wang, Mike O’Donnell

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(18)

Published: April 26, 2024

The DNA sliding clamp PCNA is a multipurpose platform for polymerases and many other proteins involved in metabolism. topologically closed ring needs to be cracked open loaded onto by loader, e.g., the well-studied pentameric ATPase complex RFC (RFC1-5). CTF18-RFC an alternative loader found recently bind leading strand polymerase ε load DNA, but its structure loading mechanism have been unknown. By cryo-EM analysis of vitro assembled human CTF18-RFC–DNA–PCNA complex, we captured seven intermediates, revealing detailed 3′-ss/dsDNA junction CTF18-RFC. Interestingly, has evolved highly mobile CTF18 AAA+ module likely lower activity, perhaps avoid competition with limit role loading. To compensate lost stability due module, unique β-hairpin motif that reaches across RFC2 interact RFC5, thereby stabilizing complex. Further, also contains separation pin locally melt from 3′-end primer; this ensures ability any junction, facilitated binding energy E-plug major groove. Our study reveals structural features contributes broader understanding loaders.

Language: Английский

Citations

8
PCNA cycling dynamics during DNA replication and repair in mammals DOI
Sukhyun Kang,

Juyeong Yoo,

Kyungjae Myung

et al.

Trends in Genetics, Journal Year: 2024, Volume and Issue: 40(6), P. 526 - 539

Published: March 13, 2024

Language: Английский

Citations

7
DCAF15 control of cohesin dynamics sustains acute myeloid leukemia DOI Creative Commons
Grant Grothusen,

Renxu Chang,

Zhendong Cao

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 3, 2024

The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal as an acute myeloid leukemia (AML)-biased dependency. Loss results in suppression AML through compromised replication fork integrity consequent accumulation DNA damage. Accordingly, loss sensitizes stress-inducing therapeutics. Mechanistically, discover that directly interacts with SMC1A protein cohesin destabilizes regulatory factors PDS5A CDCA5. CDCA5 removal precludes acetylation on chromatin, resulting uncontrolled chromatin loop extrusion, defective replication, apoptosis. Collectively, our findings uncover endogenous, cell autonomous sustaining proliferation post-translational control dynamics.

Language: Английский

Citations

4
Replisomes restrict SMC-mediated DNA-loop extrusion in vivo DOI Open Access
Qin Liao, Hugo B. Brandão, Zhongqing Ren

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 23, 2025

Abstract Structural maintenance of chromosomes (SMC) complexes organize genomes by extruding DNA loops, while replisomes duplicate entire chromosomes. These essential molecular machines must collide frequently in every cell cycle, yet how such collisions are resolved vivo remains poorly understood. Taking advantage the ability to load SMC at defined sites Bacillus subtilis genome, we engineered head-on and head-to-tail between replisome. Replisome progression was monitored marker frequency analysis, translocation time-resolved ChIP-seq Hi-C. We found that do not impede replisome progression. By contrast, restrict regardless collision orientations. Combining experimental data with simulations, determined blocked then released from chromosome. Occasionally, can bypass continue translocating. Our findings establish is a barrier SMC-mediated DNA-loop extrusion , implications for processes as chromosome segregation, repair, gene regulation require dynamic organization all organisms.

Language: Английский

Citations

0
Sister chromatid cohesion through the lens of biochemical experiments DOI
Yasuto Murayama

Current Opinion in Cell Biology, Journal Year: 2025, Volume and Issue: 93, P. 102464 - 102464

Published: Jan. 28, 2025

Language: Английский

Citations

0
Designed peptide binders and nanobodies as PROTAC starting points for targeted degradation of PCNA and BCL6 DOI
Shuai Zhao,

Jingwen Luo,

Pingping Xu

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 142667 - 142667

Published: March 1, 2025

Language: Английский

Citations

0