Resolution of sequence divergence for repeat-mediated deletions shows a polarity that is mediated by MLH1.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
25 01 2023
25 01 2023
Historique:
accepted:
04
01
2023
revised:
07
11
2022
received:
26
08
2022
pubmed:
10
1
2023
medline:
31
1
2023
entrez:
9
1
2023
Statut:
ppublish
Résumé
Repeat-mediated deletions (RMDs) are a type of chromosomal rearrangement between two homologous sequences that causes loss of the sequence between the repeats, along with one of the repeats. Sequence divergence between repeats suppresses RMDs; the mechanisms of such suppression and of resolution of the sequence divergence remains poorly understood. We identified RMD regulators using a set of reporter assays in mouse cells that test two key parameters: repeat sequence divergence and the distances between one repeat and the initiating chromosomal break. We found that the mismatch repair factor MLH1 suppresses RMDs with sequence divergence in the same pathway as MSH2 and MSH6, and which is dependent on residues in MLH1 and its binding partner PMS2 that are important for nuclease activity. Additionally, we found that the resolution of sequence divergence in the RMD product has a specific polarity, where divergent bases that are proximal to the chromosomal break end are preferentially removed. Moreover, we found that the domain of MLH1 that forms part of the MLH1-PMS2 endonuclease is important for polarity of resolution of sequence divergence. We also identified distinctions between MLH1 versus TOP3α in regulation of RMDs. We suggest that MLH1 suppresses RMDs with sequence divergence, while also promoting directional resolution of sequence divergence in the RMD product.
Identifiants
pubmed: 36620890
pii: 6976069
doi: 10.1093/nar/gkac1240
pmc: PMC9881173
doi:
Substances chimiques
DNA-Binding Proteins
0
Mismatch Repair Endonuclease PMS2
EC 3.6.1.3
Mlh1 protein, mouse
0
MutL Protein Homolog 1
EC 3.6.1.3
MutS Homolog 2 Protein
EC 3.6.1.3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
650-667Subventions
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA197506
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA240392
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA256989
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
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