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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.

 

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Read more about research in the Jackson lab.

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

Studying development to understand disease

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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