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

Abstract：

:Antigen receptor variable region exons are assembled during lymphocyte development from variable (V), diversity (D), and joining (J) gene segments. Each germ-line gene segment is flanked by recombination signal sequences (RSs). Recombination-activating gene endonuclease initiates V(D)J recombination by cleaving a pair of gene segments at their junction with flanking RSs to generate covalently sealed (hairpinned) coding ends (CEs) and blunt 5'-phosphorylated RS ends (SEs). Subsequently, nonhomologous end joining (NHEJ) opens, processes, and fuses CEs to form coding joins (CJs) and precisely joins SEs to form signal joins (SJs). DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activates Artemis endonuclease to open and process hairpinned CEs before their fusion into CJs by other NHEJ factors. Although DNA-PKcs is absolutely required for CJs, SJs are formed to variable degrees and with variable fidelity in different DNA-PKcs-deficient cell types. Thus, other factors may compensate for DNA-PKcs function in SJ formation. DNA-PKcs and the ataxia telangiectasia-mutated (ATM) kinase are members of the same family, and they share common substrates in the DNA damage response. Although ATM deficiency compromises chromosomal V(D)J CJ formation, it has no reported role in SJ formation in normal cells. Here, we report that DNA-PKcs and ATM have redundant functions in SJ formation. Thus, combined DNA-PKcs and ATM deficiency during V(D)J recombination leads to accumulation of unjoined SEs and lack of SJ fidelity. Moreover, treatment of DNA-PKcs- or ATM-deficient cells, respectively, with specific kinase inhibitors for ATM or DNA-PKcs recapitulates SJ defects, indicating that the overlapping V(D)J recombination functions of ATM and DNA-PKcs are mediated through their kinase activities.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Zha S,Jiang W,Fujiwara Y,Patel H,Goff PH,Brush JW,Dubois RL,Alt FW

doi

10.1073/pnas.1019293108

subject

Has Abstract

pub_date

2011-02-01 00:00:00

pages

2028-33

issue

5

eissn

0027-8424

issn

1091-6490

pii

1019293108

journal_volume

108

pub_type

杂志文章

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