Table 2.
Common BRCAness Genes and Evidence for PARPi sensitivity
DNA repair genes associated with homologous recombination and PARPi sensitivity
| Gene | Function in DSD repair | Evidence for PARPi sensitivity | Reference |
|---|---|---|---|
| ATM | protein kinase, DNA damage sensor, involved in repair of DSBs in heterochromatin, V(D)J class switching, meiotic recombination | +++ | Mateo J. et al., N. Engl. J. Med. 2015. |
| ATR | protein kinase, DNA damage sensor, phosporylates CHK1, BRCA1, BLM, FANCD2/FANCI, absence results in deficient HR | ++ | DeFranco C. et al., Cancer Res. 2016. |
| BAP1 | deubiquitinase required for efficient assembly of BRCA1/RAD51 at site of DSB | ++ | Goga A. et al., J Clin Oncol. 2016/Affar E. et al., Proc. Natl. Acad. Sci. USA. 2013. |
| BRCA1 | phosphoprotein that assists in 5′ to 3′ resection of DSBs, loading of RAD51 | +++ | Ledermann J. et al., N Engl J Med. 2012/Mateo J. et al., N. Engl. J. Med. 2015. |
| BRCA2 | phosphoprotein that assists with RAD51 loading | +++ | Ledermann J. et al., N Engl J Med. 2012/Mateo J. et al., N. Engl. J. Med. 2015. |
| CDK12 | regulates expression of BRCA1, FANCI, FANCD2, ATR | ++ | Ashwoth A. et al., Cancer Res. 2014./Shapiro G. et al, Cell Rep. 2016. |
| CHK2 | recruits ATM/ATR to cell cycle effectors and DNA repair machinery, phosphorylates BRCA1 | + | Fulda S. et al., Oncotarget. 2016 |
| FANCA | member of FA core complex which recruits and activates FANCD2/FANCI that co-localizes with BRCA1 | + | McCabe N. et al., Cancer Res. 2006 |
| FANCC | member of FA core complex which recruits and activates FANCD2/FANCI that co-localizes with BRCA1 | ++ | Wells S. et al., Clin Cancer Res. 2015 |
| FANCD2 | co-localizes with BRCA1 during process of homologous recombination | + | McCabe N. et al., Cancer Res. 2006/Villalona-Calero, M., Front Oncol. 2014 |
| FANCF | member of FA core complex which recruits and activates FANCD2/FANCI that co-localizes with BRCA1 | + | McCabe N. et al., Cancer Res. 2006 |
| PALB2 | promotes BRCA2 function and formation of BRCA complex | +++ | Mateo J. et al., N. Engl. J. Med. 2015. |
| NBS1 | localizes to sites of DSBs, complexes with MRE11a/Rad50, activates ATM | +++ | McNeish I. et al., Lancet Oncol. 2016 |
| WRN | 3′ to 5′ exonuclease promotes repair of DSBs | + | Helleday, T. et al., Caner Res. 2010 |
| RAD51c | assists with recruitment, stablization, and loading of RAD51 | +++ | McNeish I. et al., Lancet Oncol. 2016/Bang Y. et al., Mol Cancer Ther. 2013. |
| RAD51d | assists with recruitment, stablization of RAD51 | +++ | McNeish I. et al., Lancet Oncol. 2016 |
| MRE11A | localizes to sites of DSBs, complexes with NBS1/Rad50, activates ATM | ++ | Li D. et al., Clin Cancer Res. 2014 |
| CHK1 | protein kinase, phosporylates BLM, FANCE, FANCD2, RAD51 promoting DSB repair | ++ | Dent P. et al. Mol Pharmaol. 2012./Dent P. et al. Cancer Biol Ther. 2013 |
| BLM | RecQ helicase involved in DSB resection | + | Helleday, T. et al., Caner Res. 2010 |
+
cell culture
++
patient derived xenografts/animal models
+++
clinical trial
List of genes whose deficiency is associated with homologous repair deficiency. Evidence for PARPi sensitivity based on response to PARPi in presence of deleterious mutation(s) or inhibition of listed gene without associated mutations in BRCA1/2 or other BRCAness genes