Faculty Opinions recommendation of MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells.

2017 ◽  
Author(s):  
Mirit Aladjem ◽  
Haiqing Fu
Keyword(s):  
Stress Tolerance ◽  
Chromosome Segregation ◽  
Replication Stress ◽  
Nuclease Activity

scholarly journals MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Xianning Lai ◽  
Ronan Broderick ◽  
Valérie Bergoglio ◽  
Jutta Zimmer ◽  
Sophie Badie ◽  
...  
Keyword(s):  
Stress Tolerance ◽  
Chromosome Segregation ◽  
Replication Fork ◽  
Replication Stress ◽  
Nuclease Activity ◽  
Dna Lesions ◽  
Genome Replication ◽  
Replication Fork Progression ◽  
Nucleolytic Activity ◽  
Genomic Regions

AbstractFailure to restart replication forks stalled at genomic regions that are difficult to replicate or contain endogenous DNA lesions is a hallmark of BRCA2 deficiency. The nucleolytic activity of MUS81 endonuclease is required for replication fork restart under replication stress elicited by exogenous treatments. Here we investigate whether MUS81 could similarly facilitate DNA replication in the context of BRCA2 abrogation. Our results demonstrate that replication fork progression in BRCA2-deficient cells requires MUS81. Failure to complete genome replication and defective checkpoint surveillance enables BRCA2-deficient cells to progress through mitosis with under-replicated DNA, which elicits severe chromosome interlinking in anaphase. MUS81 nucleolytic activity is required to activate compensatory DNA synthesis during mitosis and to resolve mitotic interlinks, thus facilitating chromosome segregation. We propose that MUS81 provides a mechanism of replication stress tolerance, which sustains survival of BRCA2-deficient cells and can be exploited therapeutically through development of specific inhibitors of MUS81 nuclease activity.

scholarly journals Erratum: Corrigendum: MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Xianning Lai ◽  
Ronan Broderick ◽  
Valérie Bergoglio ◽  
Jutta Zimmer ◽  
Sophie Badie ◽  
...  
Keyword(s):  
Stress Tolerance ◽  
Chromosome Segregation ◽  
Replication Stress ◽  
Nuclease Activity

scholarly journals Structural basis for the multi-activity factor Rad5 in replication stress tolerance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Miaomiao Shen ◽  
Nalini Dhingra ◽  
Quan Wang ◽  
Chen Cheng ◽  
Songbiao Zhu ◽  
...  
Keyword(s):  
Stress Tolerance ◽  
Ubiquitin Ligase ◽  
Replication Fork ◽  
Replication Stress ◽  
Spatial Arrangement ◽  
Structural Basis ◽  
Dna Lesion ◽  
Activity Factor ◽  
Fork Regression ◽  
New Type

AbstractThe yeast protein Rad5 and its orthologs in other eukaryotes promote replication stress tolerance and cell survival using their multiple activities, including ubiquitin ligase, replication fork remodeling and DNA lesion targeting activities. Here, we present the crystal structure of a nearly full-length Rad5 protein. The structure shows three distinct, but well-connected, domains required for Rad5’s activities. The spatial arrangement of these domains suggest that different domains can have autonomous activities but also undergo intrinsic coordination. Moreover, our structural, biochemical and cellular studies demonstrate that Rad5’s HIRAN domain mediates interactions with the DNA metabolism maestro factor PCNA and contributes to its poly-ubiquitination, binds to DNA and contributes to the Rad5-catalyzed replication fork regression, defining a new type of HIRAN domains with multiple activities. Our work provides a framework to understand how Rad5 integrates its various activities in replication stress tolerance.

DNA replication stress and its impact on chromosome segregation and tumorigenesis

2019 ◽  
Vol 55 ◽  
pp. 61-69 ◽  
Author(s):  
Bi Ning Zhang ◽  
Andrés Bueno Venegas ◽  
Ian D. Hickson ◽  
Wai Kit Chu
Keyword(s):  
Dna Replication ◽  
Chromosome Segregation ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals DNA replication and spindle checkpoints cooperate during S phase to delay mitosis and preserve genome integrity

2014 ◽  
Vol 204 (2) ◽  
pp. 165-175 ◽  
Author(s):  
Maria M. Magiera ◽  
Elisabeth Gueydon ◽  
Etienne Schwob
Keyword(s):  
Dna Replication ◽  
Chromosome Segregation ◽  
Replication Stress ◽  
S Phase ◽  
Genome Integrity ◽  
Replication Forks ◽  
Mitotic Entry ◽  
Transient Activation ◽  
Spindle Checkpoints ◽  
Spindle Assembly Checkpoints

Deoxyribonucleic acid (DNA) replication and chromosome segregation must occur in ordered sequence to maintain genome integrity during cell proliferation. Checkpoint mechanisms delay mitosis when DNA is damaged or upon replication stress, but little is known on the coupling of S and M phases in unperturbed conditions. To address this issue, we postponed replication onset in budding yeast so that DNA synthesis is still underway when cells should enter mitosis. This delayed mitotic entry and progression by transient activation of the S phase, G2/M, and spindle assembly checkpoints. Disabling both Mec1/ATR- and Mad2-dependent controls caused lethality in cells with deferred S phase, accompanied by Rad52 foci and chromosome missegregation. Thus, in contrast to acute replication stress that triggers a sustained Mec1/ATR response, multiple pathways cooperate to restrain mitosis transiently when replication forks progress unhindered. We suggest that these surveillance mechanisms arose when both S and M phases were coincidently set into motion by a unique ancestral cyclin–Cdk1 complex.

scholarly journals KDM5A and KDM5B histone-demethylases contribute to HU-induced replication stress response and tolerance

Biology Open ◽  
2021 ◽  
Vol 10 (5) ◽  
Author(s):  
Solenne Gaillard ◽  
Virginie Charasson ◽  
Cyril Ribeyre ◽  
Kader Salifou ◽  
Marie-Jeanne Pillaire ◽  
...  
Keyword(s):  
Stress Response ◽  
Enzymatic Activity ◽  
Stress Tolerance ◽  
Ribonucleotide Reductase ◽  
Replication Stress ◽  
S Phase ◽  
Regulatory Subunit ◽  
Replication Forks ◽  
Histone Demethylases ◽  
Major Player

ABSTRACT KDM5A and KDM5B histone-demethylases are overexpressed in many cancers and have been involved in drug tolerance. Here, we describe that KDM5A, together with KDM5B, contribute to replication stress (RS) response and tolerance. First, they positively regulate RRM2, the regulatory subunit of ribonucleotide reductase. Second, they are required for optimal levels of activated Chk1, a major player of the intra-S phase checkpoint that protects cells from RS. We also found that KDM5A is enriched at ongoing replication forks and associates with both PCNA and Chk1. Because RRM2 is a major determinant of replication stress tolerance, we developed cells resistant to HU, and show that KDM5A/B proteins are required for both RRM2 overexpression and tolerance to HU. Altogether, our results indicate that KDM5A/B are major players of RS management. They also show that drugs targeting the enzymatic activity of KDM5 proteins may not affect all cancer-related consequences of KDM5A/B overexpression.

scholarly journals Replication stress in early S phase generates apparent micronuclei and chromosome rearrangement in fission yeast

2015 ◽  
Vol 26 (19) ◽  
pp. 3439-3450 ◽  
Author(s):  
Sarah A. Sabatinos ◽  
Nimna S. Ranatunga ◽  
Ji-Ping Yuan ◽  
Marc D. Green ◽  
Susan L. Forsburg
Keyword(s):  
Fission Yeast ◽  
Chromosome Segregation ◽  
Chromosome Rearrangement ◽  
Chromosome Instability ◽  
Replication Stress ◽  
Parent Nucleus ◽  
S Phase ◽  
Yeast Mutant ◽  
Mcm Helicase ◽  
Dna Replication Stress

DNA replication stress causes genome mutations, rearrangements, and chromosome missegregation, which are implicated in cancer. We analyze a fission yeast mutant that is unable to complete S phase due to a defective subunit of the MCM helicase. Despite underreplicated and damaged DNA, these cells evade the G2 damage checkpoint to form ultrafine bridges, fragmented centromeres, and uneven chromosome segregations that resembles micronuclei. These micronuclei retain DNA damage markers and frequently rejoin with the parent nucleus. Surviving cells show an increased rate of mutation and chromosome rearrangement. This first report of micronucleus-like segregation in a yeast replication mutant establishes underreplication as an important factor contributing to checkpoint escape, abnormal chromosome segregation, and chromosome instability.

scholarly journals Three Different Pathways Prevent Chromosome Segregation in the Presence of DNA Damage or Replication Stress in Budding Yeast

PLoS Genetics ◽  
2015 ◽  
Vol 11 (9) ◽  
pp. e1005468 ◽  
Author(s):  
Gloria Palou ◽  
Roger Palou ◽  
Fanli Zeng ◽  
Ajay A. Vashisht ◽  
James A. Wohlschlegel ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromosome Segregation ◽  
Budding Yeast ◽  
Replication Stress

scholarly journals MIF is a 3’ flap nuclease that facilitates DNA replication and promotes tumor growth

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yijie Wang ◽  
Yan Chen ◽  
Chenliang Wang ◽  
Mingming Yang ◽  
Yanan Wang ◽  
...  
Keyword(s):  
Dna Replication ◽  
Tumor Growth ◽  
Dna Synthesis ◽  
Cancer Cells ◽  
Macrophage Migration Inhibitory Factor ◽  
Replication Fork ◽  
Replication Stress ◽  
Nuclease Activity ◽  
Cell Growth Inhibition ◽  
Poor Overall Survival

AbstractHow cancer cells cope with high levels of replication stress during rapid proliferation is currently unclear. Here, we show that macrophage migration inhibitory factor (MIF) is a 3’ flap nuclease that translocates to the nucleus in S phase. Poly(ADP-ribose) polymerase 1 co-localizes with MIF to the DNA replication fork, where MIF nuclease activity is required to resolve replication stress and facilitates tumor growth. MIF loss in cancer cells leads to mutation frequency increases, cell cycle delays and DNA synthesis and cell growth inhibition, which can be rescued by restoring MIF, but not nuclease-deficient MIF mutant. MIF is significantly upregulated in breast tumors and correlates with poor overall survival in patients. We propose that MIF is a unique 3’ nuclease, excises flaps at the immediate 3’ end during DNA synthesis and favors cancer cells evading replication stress-induced threat for their growth.

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