MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks

Hayakawa, Tomohiro; Zhang, Fan; Hayakawa, Noriyo; Ohtani, Yasuko; Shinmyozu, Kaori; Nakayama, Jun‐ichi; Andreassen, Paul R.

doi:10.1242/jcs.060178

Cited by 76 publications

(101 citation statements)

References 23 publications

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“…One of the biological events in which MRG15 is involved is homologydirected DNA repair after DNA damage (21). Many proteins that control homology-directed DNA repair, such as RAD51, BRCA1, BRCA2, and PALB2, are also involved in the regulation of meiotic homologous recombination (39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

“…Many proteins that control homology-directed DNA repair, such as RAD51, BRCA1, BRCA2, and PALB2, are also involved in the regulation of meiotic homologous recombination (39)(40)(41)(42). When MRG15 is downregulated in somatic cells, localization of RAD51, BRCA2, and PALB2 to DNA damage sites is suppressed (21). However, the formation of RAD51 foci was not affected by the deletion of MRG15.…”

Section: Discussionmentioning

confidence: 99%

“…Because MRG15 plays an essential role during homology-directed DNA damage repair, SCP1, γH2AX, and ubiquitylated H2A were analyzed in spermatocytes to examine whether MRG15 is required for meiotic homologous recombination (20,21,24). However, there were no significant differences in localizations of meiosis regulating proteins between control and Mrg15 null testes (SI Appendix, Figs.…”

Section: Spermatids (mentioning

confidence: 99%

“…During spermatogenesis, histone H4 is highly acetylated before replacement of nucleosomal proteins from histones to TNPs to protamines (27). Because MRG15 is found in both HAT and HDAC complexes (13)(14)(15)(16)(17)(18)(19)(20)(21), MRG15 may be essential for postmeiotic events. To investigate whether MRG15 is involved in histone acetylation in postmeiotic spermatogenesis, acetylated histones were analyzed.…”

Section: Spermatogenesis In Mrg15mentioning

confidence: 99%

“…MRG15 specifically recognizes the methylated H3K36 and recruits polypyrimidine tract binding protein (PTB) at intronic splicing silencer elements near an exon to suppress exon insertions into mRNA (7). MRG15 is also a component of histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes and regulates transcription by balancing histone acetylation (7,(13)(14)(15)(16)(17)(18)(19)(20)(21). During spermatogenesis, before histones are replaced with transition proteins and protamines, histone H4 is highly acetylated, and the acetylation of histones is required for histone removal.…”

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MRG15 is required for pre-mRNA splicing and spermatogenesis

Iwamori

Tominaga

Sato

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Splicing can be epigenetically regulated and involved in cellular differentiation in somatic cells, but the interplay of epigenetic factors and the splicing machinery during spermatogenesis remains unclear. To study these interactions in vivo, we generated a germline deletion of MORF-related gene on chromosome 15 (MRG15), a multifunctional chromatin organizer that binds to methylated histone H3 lysine 36 (H3K36) in introns of transcriptionally active genes and has been implicated in regulation of histone acetylation, homology-directed DNA repair, and alternative splicing in somatic cells. Conditional KO (cKO) males lacking MRG15 in the germline are sterile secondary to spermatogenic arrest at the round spermatid stage. There were no significant alterations in meiotic division and histone acetylation. Specific mRNA sequences disappeared from 66 germ cell-expressed genes in the absence of MRG15, and specific intronic sequences were retained in mRNAs of 4 genes in the MRG15 cKO testes. In particular, introns were retained in mRNAs encoding the transition proteins that replace histones during sperm chromatin condensation. In round spermatids, MRG15 colocalizes with splicing factors PTBP1 and PTBP2 at H3K36me3 sites between the exons and single intron of transition nuclear protein 2 (Tnp2). Thus, our results reveal that MRG15 is essential for premRNA splicing during spermatogenesis and that epigenetic regulation of pre-mRNA splicing by histone modification could be useful to understand not only spermatogenesis but also, epigenetic disorders underlying male infertile patients.infertility | fertility defects | splicing defects | epigenetics | spermiogenesis S permatogenesis is a complex process involving several biological events and dramatic changes of chromatin structure. Male germ cells undergo stem cell self-renewal, mitotic divisions in spermatogonial proliferation, genomic rearrangement by meiotic homologous recombination at the spermatocyte stage, and morphological changes of round spermatids into elongated spermatids to form mature spermatozoa (1-3). During spermiogenesis, nucleosomal histone proteins are replaced with transition nuclear proteins (TNPs) and subsequently, protamines, the major nucleosomal proteins in spermatozoa. Moreover, epigenetic modifications, such as histone methylation, dramatically change throughout spermatogenesis (3, 4).Pre-mRNA splicing generates protein diversity and is involved in the regulation of cellular differentiation (5, 6). Recent advances have shown that histone modifications regulate alternative splicing through recruitment of splicing regulators via chromatin binding proteins, such as MORF-related gene on chromosome 15 (MRG15) (7). Histone H3 lysine 36 (H3K36) is methylated proximal to tissuespecific splicing regions (8-12). MRG15 specifically recognizes the methylated H3K36 and recruits polypyrimidine tract binding protein (PTB) at intronic splicing silencer elements near an exon to suppress exon insertions into mRNA (7). MRG15 is also a component of histone acetyltransfe...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Spermatids (mentioning

confidence: 99%

Section: Spermatogenesis In Mrg15mentioning

confidence: 99%

mentioning

confidence: 99%

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MRG15 is required for pre-mRNA splicing and spermatogenesis

Iwamori

Tominaga

Sato

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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BRCA1 alterations with additional defects in DNA damage response genes may confer chemoresistance to BRCA‐like breast cancers treated with neoadjuvant chemotherapy

Takada

Nagai

Haruta

et al. 2017

Genes Chromosomes & Cancer

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The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in BRCA1 or BRCA2 mutation carriers. As tumors with the phenotype have defects in the DNA damage response pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. The methylation and/or loss or uniparental disomy (UPD) of BRCA1 (BRCA1 alterations) and the loss or UPD of BRCA2 (BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, of the 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations (P < 0.001 and P < 0.001) and higher percentage of TP53 alterations (P < 0.001 and P < 0.001) than those without. Overall survival (OS) rates were similar between patients with or without BRCA1 or BRCA2 alterations. However, when 27 patients with BRCA1-altered tumors were classified into those with or without the loss or UPD of PALB2, PAGR1, RAD51B, FANCM, MLL4, or ERCC1/2 in tumors, patients with additional defects in DNA damage response genes had worse OS (P = 0.037, 0.045, 0.038, 0.044, 0.041, or 0.019) than those without. These defects may confer chemoresistance and predict poor outcomes in patients with BRCA1-altered breast cancer.

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The p.Ser64Leu and p.Pro104Leu missense variants of PALB2 identified in familial pancreatic cancer patients compromise the DNA damage response

et al. 2020

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PALB2 has been identified as a breast and pancreatic cancer susceptibility gene. Utilizing a targeted sequencing approach, we discovered two novel germline missense PALB2 variants c.191C>T and c.311C>T, encoding p.Ser64Leu and p.Pro104Leu, respectively, in individuals in a pancreatic cancer registry. No missense PALB2 variants from familial pancreatic cancer patients, and few PALB2 variants overall, have been functionally characterized. Given the known role of PALB2, we tested the impact of p.Ser64Leu and p.Pro104Leu variants on DNA damage responses. Neither p.Ser64Leu nor p.Pro104Leu have clear effects on interactions with BRCA1 and KEAP1, which are mediated by adjacent motifs in PALB2. However, both variants are associated with defective recruitment of PALB2, and the RAD51 recombinase downstream, to DNA damage foci. Furthermore, p.Ser64Leu and p.Pro104Leu both largely compromise DNA double‐strand break‐initiated homologous recombination, and confer increased cellular sensitivity to ionizing radiation (IR) and the poly (ADP‐ribose) polymerase (PARP) inhibitor Olaparib. Taken together, our results represent the first demonstration of functionally deleterious PALB2 missense variants associated with familial pancreatic cancer and of deleterious variants in the N‐terminus outside of the coiled‐coil domain. Furthermore, our results suggest the possibility of personalized treatments, using IR or PARP inhibitor, of pancreatic and other cancers that carry a deleterious PALB2 variant.

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MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks

Cited by 76 publications

References 23 publications

MRG15 is required for pre-mRNA splicing and spermatogenesis

MRG15 is required for pre-mRNA splicing and spermatogenesis

BRCA1 alterations with additional defects in DNA damage response genes may confer chemoresistance to BRCA‐like breast cancers treated with neoadjuvant chemotherapy

The p.Ser64Leu and p.Pro104Leu missense variants of PALB2 identified in familial pancreatic cancer patients compromise the DNA damage response

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