Proteomics

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Shieldin/CST-dependent and independent functions of 53BP1 control DNA end-joining and repair pathway choice


ABSTRACT: 53BP1 regulates DNA end-joining in lymphocytes, diversifying immune antigen receptors. This involves nucleosome-bound 53BP1 at DNA double-stranded breaks (DSBs) recruiting RIF1 and shieldin, a poorly understood DNA-binding complex. The 53BP1-RIF1-shieldin axis is pathological in BRCA1-mutated cancers, blocking homologous recombination (HR) and driving illegitimate non-homologous end-joining (NHEJ). However, how this axis regulates DNA end-joining and HR suppression remains unresolved. We investigated shieldin and its interplay with CST, a complex recently implicated in 53BP1-dependent activities. Immunophenotypically, mice lacking shieldin or CST are equivalent, with class-switch recombination co-reliant on both complexes. DNA damage-responsive signalling promotes shieldin-CST interaction, demonstrating shieldin as a DSB-specific CST adaptor. Furthermore, DNA polymerase ζ functions downstream of shieldin, establishing DNA fill-in synthesis as the physiological function of shieldin-CST. Lastly, 53BP1 suppresses HR and promotes NHEJ in BRCA1-deficient cells independently of shieldin. These findings showcase the resilience of the 53BP1 pathway, achieved through the collaboration of chromatin-bound 53BP1 complexes and DNA end-processing effector proteins.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Robert Parker  

LAB HEAD: J. Ross Chapman

PROVIDER: PXD045534 | Pride | 2024-08-27

REPOSITORIES: pride

Dataset's files

Source:
Action DRS
Ash2_SHLD.mgf Mgf
HFX0062_IPP183_C1_GST_1.raw Raw
HFX0062_IPP183_C1_GST_2.raw Raw
HXF0062_IPP183_C1_SHLD1_1.raw Raw
HXF0062_IPP183_C1_SHLD1_2.raw Raw
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