Xrs2 and Tel1 independently contribute to MR-mediated DNA tethering and replisome stability

Oh, Julyun; Lee, So Jung; Rothstein, Rodney

doi:10.1101/425942

Cited by 2 publications

(4 citation statements)

References 76 publications

(111 reference statements)

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“…We note that expression of MRE11 ‐NLS in xrs2 Δ mutant strain restores ends resection and DSB repair by SDSA but not ends tethering. This result provides further support for the role of resection rather than end tethering in proper DSB repair (Oh et al, 2018).…”

Section: Resultssupporting

confidence: 63%

Mechanisms restraining break‐induced replication at two‐ended DNA double‐strand breaks

Pham

Yan

et al. 2021

The EMBO Journal

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DNA synthesis during homologous recombination is highly mutagenic and prone to template switches. Two‐ended DNA double‐strand breaks (DSBs) are usually repaired by gene conversion with a short patch of DNA synthesis, thus limiting the mutation load to the vicinity of the DSB. Single‐ended DSBs are repaired by break‐induced replication (BIR), which involves extensive and mutagenic DNA synthesis spanning up to hundreds of kilobases. It remains unknown how mutagenic BIR is suppressed at two‐ended DSBs. Here, we demonstrate that BIR is suppressed at two‐ended DSBs by proteins coordinating the usage of two ends of a DSB: (i) ssDNA annealing proteins Rad52 and Rad59 that promote second end capture, (ii) D‐loop unwinding helicase Mph1, and (iii) Mre11‐Rad50‐Xrs2 complex that promotes synchronous resection of two ends of a DSB. Finally, BIR is also suppressed when Sir2 silences a normally heterochromatic repair template. All of these proteins are particularly important for limiting BIR when recombination occurs between short repetitive sequences, emphasizing the significance of these mechanisms for species carrying many repetitive elements such as humans.

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Section: Resultssupporting

confidence: 63%

Mechanisms restraining break‐induced replication at two‐ended DNA double‐strand breaks

Pham

Yan

et al. 2021

The EMBO Journal

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“…However, in the context of tel1-kd, the CPT sensitivity of each of the three was mitigated in comparison to the tel1∆ background. This suggests that the inactive Tel1 protein binds to, and enhances the functionality of the Mre11 complex via physical interaction as proposed previously [10,32,42]. Consistent with this idea, the effect of tel1-kd on CPT sensitivity was most pronounced in the Rad50-L1240F, mutant, which binds DNA in vitro at least 10 fold less well than Rad50-D67N or -D67Y ( Fig 5B).…”

Section: Discussionsupporting

confidence: 87%

“…Recent studies suggest that Tel1 has a structural role in stabilizing Mre11 complex DSB association that is independent of its kinase activity [10,31,32]. We found that the effects of tel1-kd versus tel1∆ on the survival of SOF mutants exposed to CPT were different, and did not strictly correlate with the ability of the mutant gene products to recruit Tel1 to DSBs.…”

Section: Molecular Phenotypes Of Rad50 Sof Mutationsmentioning

confidence: 55%

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Modeling Cancer Genomic Data in Yeast Reveals Selection Against ATM Function During Tumorigenesis

Hohl

Mojumdar

Hailemariam³

et al. 2019

Preprint

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The DNA damage response (DDR) comprises multiple functions that collectively preserve genomic integrity and suppress tumorigenesis. The Mre11 complex and ATM govern a major axis of the DDR and several lines of evidence implicate that axis in tumor suppression. Components of the Mre11 complex are mutated in approximately five percent of human cancers. Inherited mutations of complex members cause severe chromosome instability syndromes, such as Nijmegen Breakage Syndrome, which is associated with strong predisposition to malignancy. And in mice, Mre11 complex mutations are markedly more susceptible to oncogeneinduced carcinogenesis. The complex is integral to all modes of double strand break (DSB) repair and is required for the activation of ATM to effect DNA damage signaling. To understand which functions of the Mre11 complex are important for tumor suppression, we undertook mining of cancer genomic data from the clinical sequencing program at Memorial Sloan Kettering Cancer Center, which includes the Mre11 complex among the 468 genes assessed. Twenty five mutations in MRE11 and RAD50 were modeled in S.cerevisiae and in vitro. The mutations were chosen based on recurrence and conservation between human and yeast. We found that a significant fraction of tumor-borne RAD50 and MRE11 mutations exhibited separation of function phenotypes wherein Tel1/ATM activation was defective while DNA repair functions were mildly or not affected. At the molecular level, the gene products of RAD50 mutations exhibited defects in ATP binding and hydrolysis. The data reflect the importance of Rad50 ATPase activity for Tel1/ATM activation and suggest that inactivation of ATM signaling confers an advantage to burgeoning tumor cells. Hohl et al 3 Author Summary A complex network of functions is required for suppressing tumorigenesis.These include processes that regulate cell growth and differentiation, processes that repair damage to DNA and thereby prevent cancer promoting mutations and signaling pathways that lead to growth arrest and programmed cell death. The Mre11 complex influences both signaling and DNA repair. To understand its role in tumor suppression, we characterized mutations affecting members of the Mre11 complex that were uncovered through cancer genomic analyses. The data reveal that the signaling functions of the Mre11 complex are important for tumor suppression to a greater degree than its role in DNA repair.Hohl et al 4

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Xrs2 and Tel1 independently contribute to MR-mediated DNA tethering and replisome stability

Cited by 2 publications

References 76 publications

Mechanisms restraining break‐induced replication at two‐ended DNA double‐strand breaks

Mechanisms restraining break‐induced replication at two‐ended DNA double‐strand breaks

Modeling Cancer Genomic Data in Yeast Reveals Selection Against ATM Function During Tumorigenesis

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