PMID- 33453991
OWN - NLM
STAT- MEDLINE
DCOM- 20210401
LR  - 20211219
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 295
IP  - 51
DP  - 2020 Dec 18
TI  - Genetic evidence for the involvement of mismatch repair proteins, PMS2 and MLH3, 
      in a late step of homologous recombination.
PG  - 17460-17475
LID - S0021-9258(17)50633-X [pii]
LID - 10.1074/jbc.RA120.013521 [doi]
AB  - Homologous recombination (HR) repairs DNA double-strand breaks using intact 
      homologous sequences as template DNA. Broken DNA and intact homologous sequences 
      form joint molecules (JMs), including Holliday junctions (HJs), as HR 
      intermediates. HJs are resolved to form crossover and noncrossover products. A 
      mismatch repair factor, MLH3 endonuclease, produces the majority of crossovers 
      during meiotic HR, but it remains elusive whether mismatch repair factors promote 
      HR in nonmeiotic cells. We disrupted genes encoding the MLH3 and PMS2 
      endonucleases in the human B cell line, TK6, generating null MLH3(-/-) and 
      PMS2(-/-) mutant cells. We also inserted point mutations into the endonuclease 
      motif of MLH3 and PMS2 genes, generating endonuclease death MLH3(DN/DN) and 
      PMS2(EK/EK) cells. MLH3(-/-) and MLH3(DN/DN) cells showed a very similar 
      phenotype, a 2.5-fold decrease in the frequency of heteroallelic HR-dependent 
      repair of restriction enzyme-induced double-strand breaks. PMS2(-/-) and 
      PMS2(EK/EK) cells showed a phenotype very similar to that of the MLH3 mutants. 
      These data indicate that MLH3 and PMS2 promote HR as an endonuclease. The 
      MLH3(DN/DN) and PMS2(EK/EK) mutations had an additive effect on the heteroallelic 
      HR. MLH3(DN/DN)/PMS2(EK/EK) cells showed normal kinetics of gamma-irradiation-induced 
      Rad51 foci but a significant delay in the resolution of Rad51 foci and a 3-fold 
      decrease in the number of cisplatin-induced sister chromatid exchanges. The 
      ectopic expression of the Gen1 HJ re-solvase partially reversed the defective 
      heteroallelic HR of MLH3(DN/DN)/PMS2(EK/EK) cells. Taken together, we propose 
      that MLH3 and PMS2 promote HR as endonucleases, most likely by processing JMs in 
      mammalian somatic cells.
CI  - Copyright (c) 2020 (c) 2020 Rahman et al. Published by Elsevier Inc. All rights 
      reserved.
FAU - Rahman, Md Maminur
AU  - Rahman MM
AD  - Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, 
      Kyoto, Japan.
FAU - Mohiuddin, Mohiuddin
AU  - Mohiuddin M
AD  - Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, 
      Kyoto, Japan.
FAU - Shamima Keka, Islam
AU  - Shamima Keka I
AD  - Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, 
      Kyoto, Japan.
FAU - Yamada, Kousei
AU  - Yamada K
AD  - Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, 
      Kyoto, Japan.
FAU - Tsuda, Masataka
AU  - Tsuda M
AD  - Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, 
      Kyoto, Japan.
FAU - Sasanuma, Hiroyuki
AU  - Sasanuma H
AD  - Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, 
      Kyoto, Japan.
FAU - Andreani, Jessica
AU  - Andreani J
AD  - Institute for Integrative Biology of the Cell (I2BC), Commissariat a l'Energie 
      Atomique (CEA), CNRS, Universite Paris-Saclay, Gif-sur-Yvette, France.
FAU - Guerois, Raphael
AU  - Guerois R
AD  - Institute for Integrative Biology of the Cell (I2BC), Commissariat a l'Energie 
      Atomique (CEA), CNRS, Universite Paris-Saclay, Gif-sur-Yvette, France.
FAU - Borde, Valerie
AU  - Borde V
AD  - Institut Curie, CNRS, UMR3244, PSL Research University, Paris, France.
FAU - Charbonnier, Jean-Baptiste
AU  - Charbonnier JB
AD  - Institute for Integrative Biology of the Cell (I2BC), Commissariat a l'Energie 
      Atomique (CEA), CNRS, Universite Paris-Saclay, Gif-sur-Yvette, France.
FAU - Takeda, Shunichi
AU  - Takeda S
AD  - Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, 
      Kyoto, Japan. Electronic address: stakeda@rg.med.kyoto-u.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA, Cruciform)
RN  - 0 (MLH3 protein, human)
RN  - 0 (Phthalazines)
RN  - 0 (Piperazines)
RN  - EC 3.6.1.- (PMS2 protein, human)
RN  - EC 3.6.1.3 (Mismatch Repair Endonuclease PMS2)
RN  - EC 3.6.1.3 (MutL Proteins)
RN  - WOH1JD9AR8 (olaparib)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - Camptothecin/pharmacology
MH  - Cell Line
MH  - DNA Breaks, Double-Stranded
MH  - DNA Repair
MH  - DNA, Cruciform
MH  - G2 Phase
MH  - Gamma Rays
MH  - *Homologous Recombination
MH  - Humans
MH  - Mismatch Repair Endonuclease PMS2/genetics/*metabolism
MH  - MutL Proteins/genetics/*metabolism
MH  - Mutation
MH  - Phthalazines/pharmacology
MH  - Piperazines/pharmacology
PMC - PMC7762965
OTO - NOTNLM
OT  - GEN1
OT  - Holliday junction
OT  - MLH1
OT  - MLH3
OT  - MUS81
OT  - PMS2
OT  - endonuclease
OT  - homologous recombination
OT  - joint molecules
OT  - mutL homolog 1 (MLH1)
OT  - mutL homolog 3 (MLH3)
OT  - resolvase
COIS- Conflict of interest-The authors declare that they have no conflicts of interest 
      with the contents of this article. The authors declare that they have no 
      conflicts of interest with the contents of this article
EDAT- 2021/01/18 06:00
MHDA- 2021/04/02 06:00
PMCR- 2021/12/18
CRDT- 2021/01/17 20:21
PHST- 2020/03/19 00:00 [received]
PHST- 2020/09/28 00:00 [revised]
PHST- 2021/01/17 20:21 [entrez]
PHST- 2021/01/18 06:00 [pubmed]
PHST- 2021/04/02 06:00 [medline]
PHST- 2021/12/18 00:00 [pmc-release]
AID - S0021-9258(17)50633-X [pii]
AID - RA120.013521 [pii]
AID - 10.1074/jbc.RA120.013521 [doi]
PST - ppublish
SO  - J Biol Chem. 2020 Dec 18;295(51):17460-17475. doi: 10.1074/jbc.RA120.013521.