Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions

Zha, Shan; Jiang, Wenxia; Fujiwara, Yuko; Patel, Harin; Goff, Peter H.; Brush, James W.; Dubois, Richard L.; Alt, Frederick W.

doi:10.1073/pnas.1019293108

Cited by 88 publications

(93 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It acts in concert with the MRN complex (comprising the exonuclease MRE11, RAD50 and NBS1, which is formed stably only when all three proteins are present) 10, 11. Whereas DNA‐PKcs contributes to signalling DSBs at signal ends, the kinase activity of ATM, which belongs within the same family of kinases as DNA‐PKcs, can partially compensate for its function at signal ends 12, 13…”

Section: Mechanisms Of Recombination In Lymphoid Cellsmentioning

confidence: 99%

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

Procházková

Loizou

2015

Immunology

View full text Add to dashboard Cite

SummaryIn recent years, several novel congenital human disorders have been described with defects in lymphoid B‐cell and T‐cell functions that arise due to mutations in known and/or novel components of DNA repair and damage response pathways. Examples include impaired DNA double‐strand break repair, as well as compromised DNA damage‐induced signal transduction, including phosphorylation and ubiquitination. These disorders reinforce the importance of genome stability pathways in the development of lymphoid cells in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanisms of genome stability and in some cases may provide potential routes to help exploit these pathways therapeutically. Here we review the mechanisms that repair programmed DNA lesions that occur during B‐cell and T‐cell development, as well as human diseases that arise through defects in these pathways.

show abstract

Section: Mechanisms Of Recombination In Lymphoid Cellsmentioning

confidence: 99%

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

Procházková

Loizou

2015

Immunology

View full text Add to dashboard Cite

show abstract

“…Single deficiency for XLF or DNA-PKcs does not lead to major defects in SE joining during chromosomal V(D)J recombination in pro-B-cell lines (16,31,32) (Fig. 2 A-C).…”

Section: Dna-pkcs Kkinase Activity Is Required For V(d)j Sj Formationmentioning

confidence: 99%

“…Combined deficiency for ATM and DNA-PKcs in mice leads to embryonic lethality (21,22). Moreover, ATM and DNA-PKcs have redundant functions in SE joining in pro-B cells (16,23). When both proteins are inactivated, or when ATM-deficient and DNA-PKcs-deficient pro-B cells are treated with DNAPKcs and ATM specific inhibitors, respectively, SE joining is greatly impaired (16,23).…”

mentioning

confidence: 99%

“…Both point mutations in the kinase domain of DNA-PKcs (SCID mice) and elimination of DNA-PKcs expression by gene-targeted mutation abrogate CJ formation (13)(14)(15). However, in the absence of DNAPKcs, SJ formation occurs at near normal levels in embryonic stem cells and pro-B cells (15,16), but occurs at reduced levels with decreased fidelity in various nonlymphoid cells (17)(18)(19). During V(D)J recombination, DSBs activate ataxia telangiectasia mutated (ATM) kinase (4).…”

mentioning

confidence: 99%

“…Moreover, ATM and DNA-PKcs have redundant functions in SE joining in pro-B cells (16,23). When both proteins are inactivated, or when ATM-deficient and DNA-PKcs-deficient pro-B cells are treated with DNAPKcs and ATM specific inhibitors, respectively, SE joining is greatly impaired (16,23). ATM and DNA-PKcs also have redundant functions in CSR, as switching to IgG1 and IgG3 was Author contributions: V.O., V.K., X.L., C.G., B.S., S.Z., and F.W.A.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Functional redundancy between the XLF and DNA-PKcs DNA repair factors in V(D)J recombination and nonhomologous DNA end joining

Oksenych

Kumar

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

153

View full text Add to dashboard Cite

Classical nonhomologous end joining (C-NHEJ) is a major mammalian DNA double-strand break (DSB) repair pathway that is required for assembly of antigen receptor variable region gene segments by V(D)J recombination. Recombination activating gene endonuclease initiates V(D)J recombination by generating DSBs between two V (D)J coding gene segments and flanking recombination signal sequences (RS), with the two coding ends and two RS ends joined by C-NHEJ to form coding joins and signal joins, respectively. During C-NHEJ, recombination activating gene factor generates two coding ends as covalently sealed hairpins and RS ends as blunt 5′-phosphorylated DSBs. Opening and processing of coding end hairpins before joining by C-NHEJ requires the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). However, C-NHEJ of RS ends, which do not require processing, occurs relatively normally in the absence of DNA-PKcs. The XRCC4-like factor (XLF) is a C-NHEJ component that is not required for C-NHEJ of chromosomal signal joins or coding joins because of functional redundancy with ataxia telangiectasia mutated kinase, a protein that also has some functional overlap with DNA-PKcs in this process. Here, we show that XLF has dramatic functional redundancy with DNA-PKcs in the V(D)J SJ joining process, which is nearly abrogated in their combined absence. Moreover, we show that XLF functionally overlaps with DNA-PKcs in normal mouse development, promotion of genomic stability in mouse fibroblasts, and in IgH class switch recombination in mature B cells. Our findings suggest that DNA-PKcs has fundamental roles in C-NHEJ processes beyond end processing that have been masked by functional overlaps with XLF.

show abstract

ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses

Menolfi

Zha

2019

GENOME INSTAB. DIS.

Self Cite

View full text Add to dashboard Cite

Genomic integrity is critical for normal development, healthy aging and suppressing oncogenic transformation. The DNA damage response (DDR) is a complex network that is activated by DNA structural changes to preserve genome integrity. Situated at the apex of the mammalian DDR are three PI3-kinase-related protein kinases-ATM, DNA-PKcs and ATR. They are activated by different DNA lesions via direct binding to their unique sensor protein complexes (MRE11-RAD50-NBS1 for ATM, Ku70-Ku80/86 for DNA-PKcs and ATRIP-RPA for ATR) and phosphorylate a large number of partially overlapping substrates, including themselves and each other to promote DNA repair and regulate cell cycle checkpoints and tissue homeostasis. This review focuses on mouse models with deletion and point mutations of ATM, DNA-PKcs and ATR, and discusses how their activation mechanism and their kinase activity contribute to their unique, yet interactive roles in DNA repair in general and during tissue-specific development processes and how their deficiency leads to specific physiological and pathophysiological consequences.

show abstract

Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions

Cited by 88 publications

References 39 publications

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

Functional redundancy between the XLF and DNA-PKcs DNA repair factors in V(D)J recombination and nonhomologous DNA end joining

ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses

Contact Info

Product

Resources

About