TY - JOUR
T1 - BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance
AU - Nacson, Joseph
AU - Krais, John J.
AU - Bernhardy, Andrea J.
AU - Clausen, Emma
AU - Feng, Wanjuan
AU - Wang, Yifan
AU - Nicolas, Emmanuelle
AU - Cai, Kathy Q.
AU - Tricarico, Rossella
AU - Hua, Xiang
AU - DiMarcantonio, Daniela
AU - Martinez, Esteban
AU - Zong, Dali
AU - Handorf, Elizabeth
AU - Bellacosa, Alfonso
AU - Testa, Joseph R.
AU - Nussenzweig, Andre
AU - Gupta, Gaorav P.
AU - Sykes, Stephen M.
AU - Johnson, Neil
N1 - Publisher Copyright:
© 2018 The Author(s)
PY - 2018/9/25
Y1 - 2018/9/25
N2 - BRCA1 functions in homologous recombination (HR) both up- and downstream of DNA end resection. However, in cells with 53BP1 gene knockout (KO), BRCA1 is dispensable for the initiation of resection, but whether BRCA1 activity is entirely redundant after end resection is unclear. Here, we found that 53bp1 KO rescued the embryonic viability of a Brca1ΔC/ΔC mouse model that harbors a stop codon in the coiled-coil domain. However, Brca1ΔC/ΔC;53bp1−/− mice were susceptible to tumor formation, lacked Rad51 foci, and were sensitive to PARP inhibitor (PARPi) treatment, indicative of suboptimal HR. Furthermore, BRCA1 mutant cancer cell lines were dependent on truncated BRCA1 proteins that retained the ability to interact with PALB2 for 53BP1 KO induced RAD51 foci and PARPi resistance. Our data suggest that the overall efficiency of 53BP1 loss of function induced HR may be BRCA1 mutation dependent. In the setting of 53BP1 KO, hypomorphic BRCA1 proteins are active downstream of end resection, promoting RAD51 loading and PARPi resistance. Using a Brca1ΔC mouse model and a panel of BRCA1 mutant cancer cell lines, Nacson et al. show that 53BP1 loss of function induced homologous recombination and PARP inhibitor resistance is suboptimal in the absence of hypomorphic BRCA1 proteins that retain the coiled-coil domain and ability to interact with PALB2.
AB - BRCA1 functions in homologous recombination (HR) both up- and downstream of DNA end resection. However, in cells with 53BP1 gene knockout (KO), BRCA1 is dispensable for the initiation of resection, but whether BRCA1 activity is entirely redundant after end resection is unclear. Here, we found that 53bp1 KO rescued the embryonic viability of a Brca1ΔC/ΔC mouse model that harbors a stop codon in the coiled-coil domain. However, Brca1ΔC/ΔC;53bp1−/− mice were susceptible to tumor formation, lacked Rad51 foci, and were sensitive to PARP inhibitor (PARPi) treatment, indicative of suboptimal HR. Furthermore, BRCA1 mutant cancer cell lines were dependent on truncated BRCA1 proteins that retained the ability to interact with PALB2 for 53BP1 KO induced RAD51 foci and PARPi resistance. Our data suggest that the overall efficiency of 53BP1 loss of function induced HR may be BRCA1 mutation dependent. In the setting of 53BP1 KO, hypomorphic BRCA1 proteins are active downstream of end resection, promoting RAD51 loading and PARPi resistance. Using a Brca1ΔC mouse model and a panel of BRCA1 mutant cancer cell lines, Nacson et al. show that 53BP1 loss of function induced homologous recombination and PARP inhibitor resistance is suboptimal in the absence of hypomorphic BRCA1 proteins that retain the coiled-coil domain and ability to interact with PALB2.
KW - Animals
KW - Antineoplastic Agents/pharmacology
KW - BRCA1 Protein/genetics
KW - Drug Resistance, Neoplasm
KW - Fanconi Anemia Complementation Group N Protein/metabolism
KW - Female
KW - HEK293 Cells
KW - Homologous Recombination
KW - Humans
KW - Loss of Function Mutation
KW - MCF-7 Cells
KW - Mammary Neoplasms, Experimental/drug therapy
KW - Mice
KW - Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
KW - Rad51 Recombinase/metabolism
KW - Tumor Suppressor p53-Binding Protein 1/genetics
UR - http://www.scopus.com/inward/record.url?scp=85053727808&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2018.08.086
DO - 10.1016/j.celrep.2018.08.086
M3 - Article
C2 - 30257212
SN - 2211-1247
VL - 24
SP - 3513-3527.e7
JO - Cell Reports
JF - Cell Reports
IS - 13
ER -