Multiple functions of MRN in end-joining pathways during isotype class switching

Dinkelmann, Maria; Spehalski, Elizabeth I.; Stoneham, Trina; Buis, Jeffrey; Wu, Yue; Sekiguchi, JoAnn; Ferguson, David O.

doi:10.1038/nsmb.1639

Cited by 170 publications

(151 citation statements)

References 53 publications

Supporting

Mentioning

146

Contrasting

Order By: Relevance

“…Such factors are, for example, Ku70/ 80, 53BP1, and Rif1 (39)(40)(41)(42). Many classical HR factors are also implicated to be required for CSR, for example the Mre11, Rad50, and Nbs1 complex, RPA, and possibly CtIP (43)(44)(45)(46). In the absence of some c-NHEJ factor, CSR is still able to occur, although with reduced efficiency and with increased microhomology in the S-S junctions, a process called alternative end joining.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Cortizas

Verdún

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Ig class switching requires cell proliferation and is division linked, but the detailed mechanism is unknown. By analyzing the first switching cells early in the kinetics, our analysis suggested that proliferating B cells had a very short G1 phase (<3.5 h), a total cell cycle time of ∼11 h, and that Ig class switching preferentially occurred in the late G1 or early S phase. Inhibition of cyclin-dependent kinases (CDKs) caused dramatic reduction of switching rate within 6 h. This was associated with less targeting of activation-induced cytidine deaminase (AID) to the Igh locus. Interestingly, ectopically expressed nuclear AID in HeLa cells was preferentially found in the early S phase. Furthermore, in CDK2 hypomorphic cells there was reduced nuclear AID accumulation. Thus, our data are compatible with the idea that division-linked Ig class switching is in part due to CDK2-regulated AID nuclear access at the G1/S border.

show abstract

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Cortizas

Verdún

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…MRE11 participates in NHEJ pathways [21,23], which are required for class switch recombination (CSR). Complete absence of MRE11 in developing B lymphocytes causes a significant reduction in CSR, whereas MRE11 defective only in nuclease activities causes a mild CSR defect [23].…”

Section: Mre11 Rk/rk Mice and Mefs Are Hypersensitive To γ-Irmentioning

confidence: 99%

“…MRE11 nucleasedefective mice have been generated (Mre11 H129N/H129N ), defining a physiological role of the MRE11 nuclease activity in homologous recombination and the maintenance of genomic stability [30]. Mammalian MRE11 is also involved in the classical and alternative non-homologous end-joining (NHEJ) pathways [21,23]. The arginines within the MRE11 GAR motif are asymmetrically dimethylated by PRMT1 and have been shown to regulate its exonuclease activity in vitro [36,37], but the physiological significance of arginine methylation remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The MRE11 GAR motif regulates DNA double-strand break processing and ATR activation

Vogel

Coulombe

et al. 2011

Cell Res

Self Cite

View full text Add to dashboard Cite

The MRE11/RAD50/NBS1 complex is the primary sensor rapidly recruited to DNA double-strand breaks (DSBs). MRE11 is known to be arginine methylated by PRMT1 within its glycine-arginine-rich (GAR) motif. In this study, we report a mouse knock-in allele of Mre11 that substitutes the arginines with lysines in the GAR motif and generates the MRE11 RK protein devoid of methylated arginines. The Mre11 RK/RK mice were hypersensitive to γ-irradiation (IR) and the cells from these mice displayed cell cycle checkpoint defects and chromosome instability. Moreover, the Mre11 RK/RK MEFs exhibited ATR/CHK1 signaling defects and impairment in the recruitment of RPA and RAD51 to the damaged sites. The M RK RN complex formed and localized to the sites of DNA damage and normally activated the ATM pathway in response to IR. The M RK RN complex exhibited exonuclease and DNA-binding defects in vitro responsible for the impaired DNA end resection and ATR activation observed in vivo in response to IR. Our findings provide genetic evidence for the critical role of the MRE11 GAR motif in DSB repair, and demonstrate a mechanistic link between post-translational modifications at the MRE11 GAR motif and DSB processing, as well as the ATR/ CHK1 checkpoint signaling.

show abstract

“…Recently, an alternative NHEJ (alt-NHEJ) pathway has been reported, and has also been termed MMEJ or single-strand annealing (SSA) repair. It was hypothesized that cells deficient in XRCC4, a factor involved in classical NHEJ, would use the alt-NHEJ pathway for DSB repair; however, depletion of MRE11 markedly decreased alt-NHEJ, suggesting a role of MRE11 in this alternative pathway, most likely when it is in the form of the MRN complex (Dinkelmann et al, 2009;Rass et al, 2009). DNA ligase IIIα and XRCC1 were also reported to be involved in the alt-NHEJ pathway (Della-Maria et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

2015

View full text Add to dashboard Cite

The importance of chromatin modification, including histone modification and chromatin remodeling, for DNA double-strand break (DSB) repair, as well as transcription and replication, has been elucidated. Phosphorylation of H2AX to γ-H2AX is one of the first responses following DSB detection, and this histone modification is important for the DSB damage response by triggering several events, including the accumulation of DNA damage response-related proteins and subsequent homologous recombination (HR) repair. The roles of other histone modifications such as acetylation, methylation and ubiquitination have also been recently clarified, particularly in the context of HR repair. NBS1 is a multifunctional protein that is involved in various DNA damage responses. Its recently identified binding partner RNF20 is an E3 ubiquitin ligase that facilitates the monoubiquitination of histone H2B, a process that is crucial for recruitment of the chromatin remodeler SNF2h to DSB damage sites. Evidence suggests that SNF2h functions in HR repair, probably through regulation of end-resection. Moreover, several recent reports have indicated that SNF2h can function in HR repair pathways as a histone remodeler and that other known histone remodelers can also participate in DSB damage responses. On the other hand, information about the roles of such chromatin modifications and NBS1 in non-homologous end joining (NHEJ) repair of DSBs and stalled fork-related damage responses is very limited; therefore, these aspects and processes need to be further studied to advance our understanding of the mechanisms and molecular players involved.

show abstract

Multiple functions of MRN in end-joining pathways during isotype class switching

Cited by 170 publications

References 53 publications

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

The MRE11 GAR motif regulates DNA double-strand break processing and ATR activation

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

Contact Info

Product

Resources

About