scholarly journals PP4 phosphatase cooperates in recombinational DNA repair by enhancing double-strand break end resection

2018 ◽  
Author(s):  
María Teresa Villoria ◽  
Pilar Gutiérrez-Escribano ◽  
Facundo Ramos ◽  
Esmeralda Alonso-Rodríguez ◽  
Eva Merino ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Kinase Activity ◽  
Strand Break ◽  
Double Strand Break ◽  
Dna Lesion ◽  
Damage Response ◽  
End Resection ◽  
Recombinational Dna Repair

AbstractThe role of Rad53 in response to a DNA lesion is central for the accurate orchestration of the DNA damage response. Rad53 activation relies on its phosphorylation by the Mec1 kinase and its own auto-phosphorylation in a manner dependent on the adaptor Rad9. While the mechanism behind Rad53 phosphorylation and activation has been well documented, less is known about the processes that counteract its kinase activity during the response to DNA damage. Here, we describe that PP4 phosphatase dephosphorylates Rad53 during the repair of a double-strand break, a process that impacts on the phosphorylation status of multiple factors involved in the DNA damage response. PP4-dependent Rad53 dephosphorylation stimulates DNA end resection by relieving the negative effect that Rad9 exerts over the Sgs1/Dna2 exonuclease complex. Consequently, elimination of PP4 activity affects DNA resection and repair by single-strand annealing, defects that are bypassed by reducing the hyper-phosphorylation state of Rad53 observed in the absence of the phosphatase. These results confirm that Rad53 is one of the main targets of PP4 during the repair of a DNA lesion and demonstrate that the attenuation of its kinase activity during the initial steps of the repair process is essential to efficiently enhance recombinational DNA repair pathways that depend on long-range resection.

scholarly journals PP4 phosphatase cooperates in recombinational DNA repair by enhancing double-strand break end resection

2019 ◽  
Vol 47 (20) ◽  
pp. 10706-10727 ◽  
Author(s):  
María Teresa Villoria ◽  
Pilar Gutiérrez-Escribano ◽  
Esmeralda Alonso-Rodríguez ◽  
Facundo Ramos ◽  
Eva Merino ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Repair Process ◽  
Strand Break ◽  
Double Strand Break ◽  
Dna Lesion ◽  
Damage Response ◽  
End Resection ◽  
Recombinational Dna Repair

Abstract The role of Rad53 in response to a DNA lesion is central for the accurate orchestration of the DNA damage response. Rad53 activation relies on its phosphorylation by Mec1 and its own autophosphorylation in a manner dependent on the adaptor Rad9. While the mechanism behind Rad53 activation has been well documented, less is known about the processes that counteract its activity along the repair of a DNA adduct. Here, we describe that PP4 phosphatase is required to avoid Rad53 hyper-phosphorylation during the repair of a double-strand break, a process that impacts on the phosphorylation status of multiple factors involved in the DNA damage response. PP4-dependent Rad53 dephosphorylation stimulates DNA end resection by relieving the negative effect that Rad9 exerts over the Sgs1/Dna2 exonuclease complex. Consequently, elimination of PP4 activity affects resection and repair by single-strand annealing, defects that are bypassed by reducing Rad53 hyperphosphorylation. These results confirm that Rad53 phosphorylation is controlled by PP4 during the repair of a DNA lesion and demonstrate that the attenuation of its kinase activity during the initial steps of the repair process is essential to efficiently enhance recombinational DNA repair pathways that depend on long-range resection for their success.

scholarly journals Schizosaccharomyces pombe KAT5 contributes to resection and repair of a DNA double strand break

Genetics ◽  
2021 ◽  
Author(s):  
Tingting Li ◽  
Ruben C Petreaca ◽  
Susan L Forsburg
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Histone Acetyltransferase ◽  
Strand Break ◽  
Double Strand Break ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Break ◽  
Damage Response

Abstract Chromatin remodeling is essential for effective repair of a DNA double strand break. KAT5 (S. pombe Mst1, human TIP60) is a MYST family histone acetyltransferase conserved from yeast to humans that coordinates various DNA damage response activities at a DNA double strand break (DSB), including histone remodeling and activation of the DNA damage checkpoint. In S. pombe, mutations in mst1+ causes sensitivity to DNA damaging drugs. Here we show that Mst1 is recruited to DSBs. Mutation of mst1+ disrupts recruitment of repair proteins and delays resection. These defects are partially rescued by deletion of pku70, which has been previously shown to antagonize repair by homologous recombination. These phenotypes of mst1 are similar to pht1-4KR, a non-acetylatable form of histone variant H2A.Z, which has been proposed to affect resection. Our data suggest that Mst1 functions to direct repair of DSBs towards homologous recombination pathways by modulating resection at the double strand break.

scholarly journals The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

Oncogene ◽  
2012 ◽  
Vol 31 (45) ◽  
pp. 4803-4809 ◽  
Author(s):  
C Lemaître ◽  
B Fischer ◽  
A Kalousi ◽  
A-S Hoffbeck ◽  
J Guirouilh-Barbat ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Damage Response ◽  
Break Repair

scholarly journals Tetratricopeptide repeat factor XAB2 mediates the end resection step of homologous recombination

2016 ◽  
Vol 44 (12) ◽  
pp. 5702-5716 ◽  
Author(s):  
David O Onyango ◽  
Sean M Howard ◽  
Kashfia Neherin ◽  
Diana A Yanez ◽  
Jeremy M Stark
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Dna Damage Response ◽  
Strand Break ◽  
Tetratricopeptide Repeat ◽  
Intermediate Step ◽  
Damage Response ◽  
Interchromatin Granules ◽  
Chromosomal Break ◽  
End Resection

Abstract We examined the influence of the tetratricopeptide repeat factor XAB2 on chromosomal break repair, and found that XAB2 promotes end resection that generates the 3′ ssDNA intermediate for homologous recombination (HR). Namely, XAB2 is important for chromosomal double-strand break (DSB) repair via two pathways of HR that require end resection as an intermediate step, end resection of camptothecin (Cpt)-induced DNA damage, and RAD51 recruitment to ionizing radiation induced foci (IRIF), which requires end resection. Furthermore, XAB2 mediates specific aspects of the DNA damage response associated with end resection proficiency: CtIP hyperphosphorylation induced by Cpt and BRCA1 IRIF. XAB2 also promotes histone acetylation events linked to HR proficiency. From truncation mutation analysis, the capacity for XAB2 to promote HR correlates with its ability to form a complex with ISY1 and PRP19, which show a similar influence as XAB2 on HR. This XAB2 complex localizes to punctate structures consistent with interchromatin granules that show a striking adjacent-localization to the DSB marker γH2AX. In summary, we suggest that the XAB2 complex mediates DNA damage response events important for the end resection step of HR, and speculate that its adjacent-localization relative to DSBs marked by γH2AX is important for this function.

scholarly journals The Role of Small Noncoding RNA in DNA Double-Strand Break Repair

2020 ◽  
Vol 21 (21) ◽  
pp. 8039
Author(s):  
Iwona Rzeszutek ◽  
Gabriela Betlej
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Strand Break ◽  
Double Strand Break ◽  
Wide Range ◽  
Damage Response

DNA damage is a common phenomenon promoted through a variety of exogenous and endogenous factors. The DNA damage response (DDR) pathway involves a wide range of proteins, and as was indicated, small noncoding RNAs (sncRNAs). These are double-strand break-induced RNAs (diRNAs) and DNA damage response small RNA (DDRNA). Moreover, RNA binding proteins (RBPs) and RNA modifications have also been identified to modulate diRNA and DDRNA function in the DDR process. Several theories have been formulated regarding the synthesis and function of these sncRNAs during DNA repair; nevertheless, these pathways’ molecular details remain unclear. Here, we review the current knowledge regarding the mechanisms of diRNA and DDRNA biosynthesis and discuss the role of sncRNAs in maintaining genome stability.

scholarly journals The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1009067
Author(s):  
Ana Martínez-Marchal ◽  
Yan Huang ◽  
Maria Teresa Guillot-Ferriols ◽  
Mònica Ferrer-Roda ◽  
Anna Guixé ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Dna Damage Response ◽  
Strand Break ◽  
Double Strand Break ◽  
Mutant Mice ◽  
Oocyte Number ◽  
Prophase I ◽  
Damage Response

Mammalian oogonia proliferate without completing cytokinesis, forming cysts. Within these, oocytes differentiate and initiate meiosis, promoting double-strand break (DSBs) formation, which are repaired by homologous recombination (HR) causing the pairing and synapsis of the homologs. Errors in these processes activate checkpoint mechanisms, leading to apoptosis. At the end of prophase I, in contrast with what is observed in spermatocytes, oocytes accumulate unrepaired DSBs. Simultaneously to the cyst breakdown, there is a massive oocyte death, which has been proposed to be necessary to enable the individualization of the oocytes to form follicles. Based upon all the above-mentioned information, we hypothesize that the apparently inefficient HR occurring in the oocytes may be a requirement to first eliminate most of the oocytes and enable cyst breakdown and follicle formation. To test this idea, we compared perinatal ovaries from control and mutant mice for the effector kinase of the DNA Damage Response (DDR), CHK2. We found that CHK2 is required to eliminate ~50% of the fetal oocyte population. Nevertheless, the number of oocytes and follicles found in Chk2-mutant ovaries three days after birth was equivalent to that of the controls. These data revealed the existence of another mechanism capable of eliminating oocytes. In vitro inhibition of CHK1 rescued the oocyte number in Chk2-/- mice, implying that CHK1 regulates postnatal oocyte death. Moreover, we found that CHK1 and CHK2 functions are required for the timely breakdown of the cyst and to form follicles. Thus, we uncovered a novel CHK1 function in regulating the oocyte population in mice. Based upon these data, we propose that the CHK1- and CHK2-dependent DDR controls the number of oocytes and is required to properly break down oocyte cysts and form follicles in mammals.

scholarly journals MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair

2010 ◽  
Vol 30 (14) ◽  
pp. 3582-3595 ◽  
Author(s):  
Girdhar G. Sharma ◽  
Sairei So ◽  
Arun Gupta ◽  
Rakesh Kumar ◽  
Christelle Cayrou ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Histone H4 ◽  
Dsb Repair ◽  
Altered Expression ◽  
Damage Response ◽  
Break Repair

ABSTRACT The human MOF gene encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac). Here we show that reduced levels of H4K16ac correlate with a defective DNA damage response (DDR) and double-strand break (DSB) repair to ionizing radiation (IR). The defect, however, is not due to altered expression of proteins involved in DDR. Abrogation of IR-induced DDR by MOF depletion is inhibited by blocking H4K16ac deacetylation. MOF was found to be associated with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a protein involved in nonhomologous end-joining (NHEJ) repair. ATM-dependent IR-induced phosphorylation of DNA-PKcs was also abrogated in MOF-depleted cells. Our data indicate that MOF depletion greatly decreased DNA double-strand break repair by both NHEJ and homologous recombination (HR). In addition, MOF activity was associated with general chromatin upon DNA damage and colocalized with the synaptonemal complex in male meiocytes. We propose that MOF, through H4K16ac (histone code), has a critical role at multiple stages in the cellular DNA damage response and DSB repair.

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