RPA shields inherited DNA lesions for post-mitotic DNA synthesis

Lezaja, Aleksandra; Παναγόπουλος, Ανδρέας; Wen, Yanlin; Carvalho, Edison Samir Mascarelhas; Imhof, Ralph; Altmeyer, Matthias

doi:10.1038/s41467-021-23806-5

Cited by 20 publications

(22 citation statements)

References 83 publications

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“…S6B,C " type="url"/> ) demonstrating normal DNA damage repair kinetics in mutant spermatocytes and suggesting the aberrant γH2AX signal is not a result of persistent or recurring DNA damage. Previous work has suggested that some DNA double strand breaks may not be marked by RPA ( Lezaja et al, 2021 ); thus, as a secondary assessment, we examined relative levels of the 9-1-1 DNA damage recognition complex as indicated by RAD9 ( Parrilla-Castellar et al, 2004 ) and activation of NHEJ marked by Ku80 ( Fell and Schild-Poulter, 2015 ; Ma et al, 2018 ) ( ).…”

Section: Resultsmentioning

confidence: 99%

ADAD2 regulates heterochromatin in meiotic and post-meiotic male germ cells via translation of MDC1

Chukrallah

Badrinath

Vittor

et al. 2022

Journal of Cell Science

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Male germ cells establish a unique heterochromatin domain, the XY-body, early in meiosis. How this domain is maintained through the end of meiosis and into post-meiotic germ cell differentiation is poorly understood. ADAD2 is a late meiotic male germ cell-specific RNA-binding protein, loss of which leads to post-meiotic germ cell defects. Analysis of ribosome association in Adad2 mouse mutants revealed defective translation of Mdc1, a key regulator of XY-body formation, late in meiosis. As a result, Adad2 mutants show normal establishment but failed maintenance of the XY-body. Observed XY-body defects are concurrent with abnormal autosomal heterochromatin and ultimately lead to severely perturbed post-meiotic germ cell heterochromatin and cell death. These findings highlight the requirement of ADAD2 for Mdc1 translation, the role of MDC1 in maintaining meiotic male germ cell heterochromatin and the importance of late meiotic heterochromatin for normal post-meiotic germ cell differentiation.

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Section: Resultsmentioning

confidence: 99%

ADAD2 regulates heterochromatin in meiotic and post-meiotic male germ cells via translation of MDC1

Chukrallah

Badrinath

Vittor

et al. 2022

Journal of Cell Science

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“…The converse may be true for POLQ – / – clones undergoing a telomere-driven crisis, so that cell cycle progression and population doubling rates may be expedited, with reduced opportunity for corrective DNAR that safeguards genomic integrity. As POLQ plays an important role in the rescue of intermediates of aborted HR that materialize late in the cell cycle ( 22 ), frustration of TMEJ may also deter cell cycle pausing pre-mitosis, so that chromosomal damage persists ( 98 , 99 ), is extruded into micronuclei (MN) ( 100 ) or triggers apoptosis without suspension of proliferation. In concert with the skewed distributions of inter- and intra-chromosomal telomere fusions (Figure 3A ), POLQ deficiency supports long-range DNA recombinations that precipitate genomic heterogeneity ( 100 ), manifest in the polyclonal post-crisis populations ( Supplementary Figure S5 ).…”

Section: Discussionmentioning

confidence: 99%

POLQ suppresses genome instability and alterations in DNA repeat tract lengths

et al. 2022

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DNA polymerase theta (POLQ) is a principal component of the alternative non-homologous end-joining (ANHEJ) DNA repair pathway that ligates DNA double-strand breaks. Utilizing independent models of POLQ insufficiency during telomere-driven crisis, we found that POLQ–/– cells are resistant to crisis-induced growth deceleration despite sustaining inter-chromosomal telomere fusion frequencies equivalent to wild-type (WT) cells. We recorded longer telomeres in POLQ–/– than WT cells pre- and post-crisis, notwithstanding elevated total telomere erosion and fusion rates. POLQ–/– cells emerging from crisis exhibited reduced incidence of clonal gross chromosomal abnormalities in accordance with increased genetic heterogeneity. High-throughput sequencing of telomere fusion amplicons from POLQ-deficient cells revealed significantly raised frequencies of inter-chromosomal fusions with correspondingly depreciated intra-chromosomal recombinations. Long-range interactions culminating in telomere fusions with centromere alpha-satellite repeats, as well as expansions in HSAT2 and HSAT3 satellite and contractions in ribosomal DNA repeats, were detected in POLQ–/– cells. In conjunction with the expanded telomere lengths of POLQ–/– cells, these results indicate a hitherto unrealized capacity of POLQ for regulation of repeat arrays within the genome. Our findings uncover novel considerations for the efficacy of POLQ inhibitors in clinical cancer interventions, where potential genome destabilizing consequences could drive clonal evolution and resistant disease.

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“…These RPA foci colocalize with single stranded DNA that escaped the previous cell cycle, and they predominantly associate with telomeric regions. Knocking down RAD52 reduced G1-associated RPA foci indicating that these regions might have been primed by RAD52 in the previous mitosis [ 154 ].…”

Section: Mechanisms For Managing Replication Stressmentioning

confidence: 99%

Safeguarding DNA Replication: A Golden Touch of MiDAS and Other Mechanisms

Nachar

Rosselli

2022

IJMS

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DNA replication is a tightly regulated fundamental process allowing the correct duplication and transfer of the genetic information from the parental cell to the progeny. It involves the coordinated assembly of several proteins and protein complexes resulting in replication fork licensing, firing and progression. However, the DNA replication pathway is strewn with hurdles that affect replication fork progression during S phase. As a result, cells have adapted several mechanisms ensuring replication completion before entry into mitosis and segregating chromosomes with minimal, if any, abnormalities. In this review, we describe the possible obstacles that a replication fork might encounter and how the cell manages to protect DNA replication from S to the next G1.

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RPA shields inherited DNA lesions for post-mitotic DNA synthesis

Cited by 20 publications

References 83 publications

ADAD2 regulates heterochromatin in meiotic and post-meiotic male germ cells via translation of MDC1

ADAD2 regulates heterochromatin in meiotic and post-meiotic male germ cells via translation of MDC1

POLQ suppresses genome instability and alterations in DNA repeat tract lengths

Safeguarding DNA Replication: A Golden Touch of MiDAS and Other Mechanisms

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