论文信息 - Filling in the gaps in PARP inhibitor-induced synthetic lethality

Filling in the gaps in PARP inhibitor-induced synthetic lethality

ABSTRACT Tumors with loss of breast cancer type 1 susceptibility protein (BRCA1) are homologous recombination (HR) deficient and hypersensitive to poly(ADP-ribose) polymerase inhibitors (PARPi). However, these tumors may restore HR and acquire PARPi resistance via loss of end-protection of DNA double-strand breaks. We found that loss of nuclear DNA ligase III resensitizes HR-restored BRCA1-deficient cells to PARPi by exposing post-replicative single-stranded DNA (ssDNA) gaps. Our work, and that of others, identifies ssDNA gaps as a key determinant of PARPi response.

J. Jonkers | Mariana Paes Dias

[1] M. Wood,et al. Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells. , 2021, Molecular cell.

[2] J. Bartek,et al. Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps. , 2021, Molecular cell.

[3] Alberto Ciccia,et al. REV1-Polζ maintains the viability of homologous recombination-deficient cancer cells through mutagenic repair of PRIMPOL-dependent ssDNA gaps. , 2021, Molecular cell.

[4] J. Bartek,et al. Loss of Nuclear DNA Ligase III Reverts PARP Inhibitor Resistance in BRCA1/53BP1 Double-deficient Cells by Exposing ssDNA Gaps , 2021, bioRxiv.

[5] S. Ganesan,et al. Understanding and overcoming resistance to PARP inhibitors in cancer therapy , 2021, Nature Reviews Clinical Oncology.

[6] S. Cantor,et al. Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency. , 2021, Molecular cell.

[7] S. Cantor,et al. Replication gaps underlie BRCA-deficiency and therapy response , 2019, bioRxiv.

[8] M. Lopes,et al. Rad51 protects nascent DNA from Mre11 dependent degradation and promotes continuous DNA synthesis , 2010, Nature Structural &Molecular Biology.

[9] M. Lopes,et al. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. , 2006, Molecular cell.