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10.02.20 Role of the protein PALB2 in the DNA-damage response

last modified Feb 10, 2020 10:39 AM
The Jackson lab are piecing together the puzzle of how cancer cells become resistant to the PARP inhibitors designed to target BRCA1/2 deficient cells. They describe the role of PALB2 in protein interactions that form the DNA damage response
10.02.20 Role of the protein PALB2 in the DNA-damage response

PALB2 foci (green)

PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1

Belotserkovskaya R et al. (2020) Nature Communications 11, 819. DOI: 10.1038/s41467-020-14563-y.



Abstract from the paper

Loss of functional BRCA1 protein leads to defects in DNA double-strand break (DSB) repair by homologous recombination (HR) and renders cells hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors used to treat BRCA1/2-deficient cancers. However, upon chronic treatment of BRCA1-mutant cells with PARP inhibitors, resistant clones can arise via several mechanisms, including loss of 53BP1 or its downstream co-factors.

Defects in the 53BP1 axis partially restore the ability of a BRCA1-deficient cell to form RAD51 filaments at resected DSBs in a PALB2- and BRCA2-dependent manner, and thereby repair DSBs by HR. Exactly how loss of 53BP1 rescues RAD51 loading in BRCA1-deficient cells is not mechanistically understood.

Our findings support a model whereby depleting 53BP1 in BRCA1-null cells restores PALB2 accrual at DSBs in a manner dependent on an interaction between PALB2’s Chromatin Associated Motif and the nucleosome acidic patch region, which in 53BP1-expressing cells is bound by 53BP1’s ubiquitin-directed recruitment domain.



Read more about research in the Jackson lab.

Hear Steve Jackson describe the science behind the PARP inhibitors in this short video.

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The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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