Time-Dependent Predominance of Nonhomologous DNA End-Joining Pathways during Embryonic Development in Mice

Chiruvella, Kishore K.; Sebastian, Robin; Sharma, Sheetal; Karande, Anjali A.; Choudhary, Bibha; Raghavan, Sathees C.

doi:10.1016/j.jmb.2012.01.029

Cited by 48 publications

(49 citation statements)

References 67 publications

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“…Studies in mammalian cells have implicated DNA ligase III (Lig3) as the major alt-NHEJ ligase (Audebert et al 2004;Wang et al 2005;Sallmyr et al 2008;Simsek et al 2011;Chiruvella et al 2012). As a cofactor of Lig3, XRCC1 is also suggested to be involved (Audebert et al 2004;Saribasak et al 2011), although more recent studies suggest that XRCC1 may be dispensable (Boboila et al 2012;Han et al 2012).…”

Section: Alt-nhejmentioning

confidence: 99%

Repair of Double-Strand Breaks by End Joining

Chiruvella

Liang

Wilson

2013

Cold Spring Harbor Perspectives in Biology

336

280

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Section: Alt-nhejmentioning

confidence: 99%

Repair of Double-Strand Breaks by End Joining

Chiruvella

Liang

Wilson

2013

Cold Spring Harbor Perspectives in Biology

336

280

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“…CSR is no exception, and even if AID-induced DSBs in S regions would appear fairly amenable to repair by A-EJ, C-NHEJ is necessary for efficient CSR and cannot be adequately replaced by A-EJ. Recently, variations between relative C-NHEJ and A-EJ activities assessed in vitro with cell free extracts prepared from mouse embryos at different stages of development, suggested a role for A-EJ during embryogenesis [285]. However in vivo experiments are required to confirm and confidently interpret these findings.…”

Section: A-ej: the "No Pathway" Optionmentioning

confidence: 99%

Alternative end-joining pathway(s): Bricolage at DNA breaks

et al. 2014

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To cope with DNA double strand break (DSB) genotoxicity, cells have evolved two main repair pathways: homologous recombination which uses homologous DNA sequences as repair templates, and non-homologous Ku-dependent end-joining involving direct sealing of DSB ends by DNA ligase IV (Lig4). During the last two decades a third player most commonly named alternative end-joining (A-EJ) has emerged, which is defined as any Ku- or Lig4-independent end-joining process. A-EJ increasingly appears as a highly error-prone bricolage on DSBs and despite expanding exploration, it still escapes full characterization. In the present review, we discuss the mechanism and regulation of A-EJ as well as its biological relevance under physiological and pathological situations, with a particular emphasis on chromosomal instability and cancer. Whether or not it is a genuine DSB repair pathway, A-EJ is emerging as an important cellular process and understanding A-EJ will certainly be a major challenge for the coming years.

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“…DNA DSB's pose a serious threat to both cell viability and genome stability if left unrepaired or repaired incorrectly, and could potentially lead to permanent damage with resulting negative consequences for gamete health (Petrillo et al , 2011; Summers et al , 2011). Two major pathways can repair DNA DSB's: Non-Homologous End Joining (NHEJ) (Chiruvella et al , 2012) and Homologous Recombination (HR) (Scully et al , 1997). Key signaling molecules involved in NHEJ repair include the X-ray repair complementing defective repair in Chinese hamster cells 6 and 5 (XRCC6 and XRCC5) heterodimer which recognizes and binds to the DSB, recruiting protein kinase DNA-activated, catalytic polypeptide (PRKDC) to the DSB ends (Calsou et al , 2003; Dobbs et al , 2010; Chiruvella et al , 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Two major pathways can repair DNA DSB's: Non-Homologous End Joining (NHEJ) (Chiruvella et al , 2012) and Homologous Recombination (HR) (Scully et al , 1997). Key signaling molecules involved in NHEJ repair include the X-ray repair complementing defective repair in Chinese hamster cells 6 and 5 (XRCC6 and XRCC5) heterodimer which recognizes and binds to the DSB, recruiting protein kinase DNA-activated, catalytic polypeptide (PRKDC) to the DSB ends (Calsou et al , 2003; Dobbs et al , 2010; Chiruvella et al , 2012). During HR, breast cancer type 1 (BRCA1) can be phosphorylated by ATM and co-localizes with RAD51 recombinase (RAD51) at the site of DNA damage to induce DSB repair (Scully et al , 1997).…”

Section: Introductionmentioning

confidence: 99%

Enhanced susceptibility of ovaries from obese mice to 7,12-dimethylbenz[a]anthracene-induced DNA damage

Ganesan

Nteeba

Keating

2014

Toxicology and Applied Pharmacology

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7,12-dimethylbenz[a]anthracene (DMBA) depletes ovarian follicles and induces DNA damage in extra-ovarian tissues, thus, we investigated ovarian DMBA-induced DNA damage. Additionally, since obesity is associated with increased offspring birth defect incidence, we hypothesized that a DMBA-induced DNA damage response (DDR) is compromised in ovaries from obese females. Wild type (lean) non agouti (a/a) and KK.Cg-Ay/J heterozygote (obese) mice were dosed with sesame oil or DMBA (1mg/kg; intraperitoneal injection) at 18 wks of age, for 14 days. Total ovarian RNA and protein were isolated and abundance of Ataxia telangiectasia mutated (Atm), X-ray repair complementing defective repair in chinese hamster cells 6 (Xrcc6), Breast cancer type 1 (Brca1), Rad 51 homolog (Rad51), Poly [ADP-ribose] polymerase 1 (Parp1) and Protein kinase, DNA-activated, catalytic polypeptide (Prkdc) were quantified by RT-PCR or Western blot. Phosphorylated histone H2AX (γH2AX) level was determined by Western blotting. Obesity decreased (P < 0.05) basal protein abundance of PRKDC and BRCA1 proteins but increased (P < 0.05) γH2AX and PARP1 proteins. Ovarian ATM, XRCC6, PRKDC, RAD51 and PARP1 proteins were increased (P < 0.05) by DMBA exposure in lean mice. A blunted DMBA-induced increase (P < 0.05) in XRCC6, PRKDC, RAD51 and BRCA1 was observed in ovaries from obese mice, relative to lean counterparts. Taken together, DMBA exposure induced γH2AX as well as the ovarian DDR, supporting that DMBA causes ovarian DNA damage. Additionally, ovarian DDR was partially attenuated in obese females raising concern that obesity may be an additive factor during chemical-induced ovotoxicity.

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Time-Dependent Predominance of Nonhomologous DNA End-Joining Pathways during Embryonic Development in Mice

Cited by 48 publications

References 67 publications

Repair of Double-Strand Breaks by End Joining

Repair of Double-Strand Breaks by End Joining

Alternative end-joining pathway(s): Bricolage at DNA breaks

Enhanced susceptibility of ovaries from obese mice to 7,12-dimethylbenz[a]anthracene-induced DNA damage

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