Introduction
Genes that when mutated cause Fanconi anemia (FA) and/or influence breast cancer (BrCa) susceptibility functionally converge on a homology-directed DNA damage repair process [
1]. That is, 15 FA genes (
FANCs) and genes with high-penetrance, moderate-penetrance or low-penetrance mutations for BrCa encode for proteins cooperating in a defined FA/BrCa signaling pathway [
2‐
6]. Remarkably, germline bi-allelic and mono-allelic loss-of-function mutations in four of these genes cause FA and BrCa, respectively:
FANCD1/BRCA2 [
7,
8],
FANCJ/BRIP1 [
9‐
12],
FANCN/PALB2 [
13‐
15], and the recently identified FA-like/BrCa mutated gene
FANCO/
RAD51C [
3,
4]. These observations partially endorse perturbation of the DNA damage response as fundamental in leading to breast carcinogenesis. In addition to the main effects on susceptibility, variation in
RAD51 - a gene encoding for a component of this pathway and paralog of
RAD51C - modifies BrCa risk among
BRCA2 but not
BRCA1 mutation carriers [
16]. Notably, RAD51 interacts with BRCA1 and BRCA2 [
17,
18] to regulate double-strand breaks repair by homologous recombination [
19].
While genes with low-penetrance and/or modifier alleles can be linked to diverse biological processes, the FA/BrCa pathway is still incomplete [
2,
20]. To gain deeper insight into the molecular and functional FA/BrCa wiring diagram and the fundamental biological process(es) influencing cancer risk, we screened for novel protein physical interactions of known pathway components. Consistent with previous results on protein complex memberships [
21,
22], we identified a physical interaction between PALB2 and MRG15. Results from the analysis of MRG15/
MORF4L1 in unclassified FA patients and familial BrCa cases did not reveal pathological alterations; nonetheless, a weak modifier effect among carriers of
BRCA2 mutations cannot be ruled out.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
The project was conceived and the experiments and data analyses were coordinated by JS and MAP. The Y2H design and screens were performed by GM, CAM, LG-B and MAP. The co-AP/co-IP assays, biochemical and/or cell biology studies of FA/BrCa pathway components were performed by GM, CAM, LG-B, HA, FKP, RD and MAP. The studies of MORF4L1/MRG15 in MEFs and the co-AP assays were performed by ET, OMP-S and KT. The studies of mitomycin-C and γ-radiation sensitivity, and FANCD2 monoubiquitinylation were performed by MB, MJR, MC, GH and JS. Statistical analyses were performed by NB, DC and MAP with the support of LM and ACA. The studies in C. elegans were performed by MP and JC. MORF4L1 sequencing was carried out by SS, AR and NR in the United Kingdom, and CL, IB, JBr, JF-R and MAP in Spain. The study of cell lines from FA patients was performed by JK, KN and DS. The study of CIMBA carriers was coordinated and executed by DFE, LM, ACA and GC-T. iPLEX genotyping was performed by XC and JBee. Classification of BRCA1/2 mutations was performed by SH and OMS. DNA samples and clinical data of carriers were contributed by: DFE, SP, MC, CTO, DF, RP, DGE, FL, RE, LI, CC, RD, K-RO, JC, FD, SH, CB, PJM and MP (EMBRACE); PP, SM, BP, DF, GR, MB, AV, BP, LO, ALP, AS, LB and PR (CONSIT TEAM); SH, AS, XC, JB and GC-T (kConFab); MAR, SV, MAT-L, MPV, CJA, DB, MGEMA, TAO, MJB, HEJM-H and FBLH (HEBON); DEG, SB, EMJ, AM, JLH and MBD (BCFR); KH, AB, JR, GB-B, HE and MS-A (SWE-BRCA); BK, YL, RM and EF (SMC); SMD, KLN and TRB (UPENN); OTJ (ILUH); FJC, XW and ZF (Mayo); TC (HCSC); TH and HN (HEBCS); UH and DT (DKFZ); MAC (PBCS); AKG (FCCC); ENI, RJ, OMS, DS-L, SM, CV-P, LC, AP, Y-JB, NU, J-PP, PV, SFF, M-AC-R and IM (BFBOCC and GEMO Study Collaborators); and CL, IB and J Brunet (ICO). AO, JBen, JBu and VM helped with data analysis and interpretation, and contributed with reagents. The manuscript was written by MAP. All authors read and approved the final manuscript.