Exploring the link between MORF4L1 and risk of breast cancer

Abstract

IntroductionProteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens.MethodsProtein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk.ResultsA previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively.ConclusionsWhile the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

PALB2: The hub of a network of tumor suppressors involved in DNA damage responses

“…The interaction of PALB2 with MRG15 has been identified both in protein complexes isolated from cells, using mass spectrometry [65, 71], and through yeast-two hybrid screens [72]. This interaction is of particular interest given the potential challenges of recognizing and repairing DNA damage in the context of highly packaged chromatin (reviewed in [105, 106]).…”

“…Multiple reports suggest that MRG15 has some role in PALB2-dependent repair of DNA by HR, but differ in the purported role of MRG15 in this process [65, 71, 72]. Sy et al (2009) [71] suggest that knockdown of MRG15, or deletion of a broad region of PALB2 (amino acids 611–764) that contains the MRG15-interacting domain, leads to hyper-recombination.…”

“…PALB2 also interacts with MRG15 [65, 71, 72], which is a component of various histone modifying complexes. This interaction represents a potential interface between chromatin regulation and DNA repair, as detailed in Section 3.2 .…”

Proteasome regulation of the chromodomain protein MRG-1 controls the balance between proliferative fate and differentiation in theC. elegansgerm line

“…Additionally, it has been shown in other organisms, including Drosophila, yeast and humans, that MORF/ MRG family proteins are associated with complexes that are involved in the activation or repression of target gene transcription. Some of these target genes, including B-myb, cdc-2 and p53, are known to control cell proliferation (Alekseyenko et al, 2006;Chen et al, 2011Chen et al, , 2010Kind et al, 2008;Leung et al, 2001;Martrat et al, 2011;Pena and Pereira-Smith, 2007;Peña et al, 2011;Smith et al, 2005;Tominaga et al, 2003). Therefore, MRG-1 could both promote the expression of proteins necessary for proliferation and repress the expression of proteins necessary for differentiation.…”

Human Tip60 (NuA4) Complex and Cancer

“…No alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and Breast Cancer (BrCa) familial cases. No significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified (Martrat et al, 2011). Yeast Eaf3 is a shared component of the NuA4 complex and Rpd3 histone deacetylase complex.…”