The MRN-CtIP Pathway Is Required for Metaphase Chromosome Alignment

Rozier, Lorène; Guo, Yige; Peterson, Shaun; Mai, Sabine; Baer, Richard; Gautier, Jean; Mao, Yinghui

doi:10.1016/j.molcel.2013.01.023

Cited by 17 publications

(27 citation statements)

References 58 publications

(89 reference statements)

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“…In line with this hypothesis, RAD50-depleted NIH3T3 fibroblasts exhibited a pronounced delay in the mitotic duration between prometaphase onset and cytokinetic abscission. A similar observation has been made recently in Xenopus eggs where MRE11 knockdown, probably affecting RAD50 levels, or inhibition with the MRN inhibitor mirin caused a significant metaphase delay (42). Collectively, these data suggest a previously unanticipated role of RAD50 in the regulation of mitosis.…”

Section: Discussionsupporting

confidence: 86%

Protective role of RAD50 on chromatin bridges during abnormal cytokinesis

et al. 2013

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Faithful chromosome segregation is required for preserving genomic integrity. Failure of this process may entail chromatin bridges preventing normal cytokinesis. To test whether RAD50, a protein normally involved in DNA double-strand break repair, is involved in abnormal cytokinesis and formation of chromatin bridges, we used immunocytochemical and protein interaction assays. RAD50 localizes to chromatin bridges during aberrant cytokinesis and subsequent stages of the cell cycle, either decorating the entire bridge or focally accumulating at the midbody zone. Ionizing radiation led to an ∼4-fold increase in the rate of chromatin bridges in an ataxia telangiectatica mutated (ATM)-dependent manner in human RAD50-proficient fibroblasts but not in RAD50-deficient cells. Cells with a RAD50-positive chromatin bridge were able to continue cell cycling and to progress through S phase (44%), whereas RAD50 knockdown caused a deficiency in chromatin bridges as well as an ∼4-fold prolonged duration of mitosis. RAD50 colocalized and directly interacted with Aurora B kinase and phospho-histone H3, and Aurora B kinase inhibition led to a deficiency in RAD50-positive bridges. Based on these observations, we propose that RAD50 is a crucial factor for the stabilization and shielding of chromatin bridges. Our study provides evidence for a hitherto unknown role of RAD50 in abnormal cytokinesis.

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Section: Discussionsupporting

confidence: 86%

Protective role of RAD50 on chromatin bridges during abnormal cytokinesis

et al. 2013

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“…Regulation of kinetochore-microtubule attachment and chromosome alignment by DDR factors has been previously reported (Rozier et al, 2013). Our data suggests that ubiquitin signaling may mediate DDR regulation of the kinetochore.…”

Section: Discussionmentioning

confidence: 93%

Quantitative Proteomic Atlas of Ubiquitination and Acetylation in the DNA Damage Response

et al. 2015

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Summary Execution of the DNA damage response (DDR) relies upon a dynamic array of protein modifications. Using quantitative proteomics, we have globally profiled ubiquitination, acetylation, and phosphorylation in response to ultraviolet and ionizing radiation. To improve acetylation site profiling, we developed the strategy FACET-IP. Our datasets of 33,500 ubiquitination and 16,740 acetylation sites provide valuable insight into DDR remodeling of the proteome. We find that K6- and K33-linked polyubiquitination undergo bulk increases in response to DNA damage, raising the possibility that these linkages are largely dedicated to DDR function. We also show that Cullin Ring Ligases mediate 10% of DNA damage induced ubiquitination events and that EXO1 is an SCF-Cyclin F substrate in the response to UV radiation. Our extensive datasets uncover additional regulated sites on known DDR players such as PCNA and identify previously unknown DDR targets such as CENPs, underscoring the broad impact of the DDR on cellular physiology.

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“…32 We also used live imaging to monitor spindle formation in oocytes expressing MAP4-EGFP and H2B-CHERRY (Fig. S4D and Movie 5).…”

Section: Mre11 Controls Chromosome Segregation and Integritymentioning

confidence: 99%

DNA damage response during mouse oocyte maturation

Mayer

Baran

Sakakibara³

et al. 2016

Cell Cycle

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Because low levels of DNA double strand breaks (DSBs) appear not to activate the ATM-mediated prophase I checkpoint in full-grown oocytes, there may exist mechanisms to protect chromosome integrity during meiotic maturation. Using live imaging we demonstrate that low levels of DSBs induced by the radiomimetic drug Neocarzinostatin (NCS) increase the incidence of chromosome fragments and lagging chromosomes but do not lead to APC/C activation and anaphase onset delay. The number of DSBs, represented by gH2AX foci, significantly decreases between prophase I and metaphase II in both control and NCS-treated oocytes. Transient treatment with NCS increases >2-fold the number of DSBs in prophase I oocytes, but less than 30% of these oocytes enter anaphase with segregation errors. MRE11, but not ATM, is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of gH2AX foci in metaphase II. Compromised DNA integrity in mirin-treated oocytes indicates a role for MRE11 in chromosome integrity during meiotic maturation.

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The MRN-CtIP Pathway Is Required for Metaphase Chromosome Alignment

Cited by 17 publications

References 58 publications

Protective role of RAD50 on chromatin bridges during abnormal cytokinesis

Protective role of RAD50 on chromatin bridges during abnormal cytokinesis

Quantitative Proteomic Atlas of Ubiquitination and Acetylation in the DNA Damage Response

DNA damage response during mouse oocyte maturation

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