Insights into DNA cleavage by MutL homologs from analysis of conserved motifs in eukaryotic Mlh1.
DNA mismatch repair
MutL
endonuclease activity
Journal
BioEssays : news and reviews in molecular, cellular and developmental biology
ISSN: 1521-1878
Titre abrégé: Bioessays
Pays: United States
ID NLM: 8510851
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
revised:
02
06
2023
received:
11
02
2023
accepted:
15
06
2023
pmc-release:
01
09
2024
medline:
28
8
2023
pubmed:
10
7
2023
entrez:
9
7
2023
Statut:
ppublish
Résumé
MutL family proteins contain an N-terminal ATPase domain (NTD), an unstructured interdomain linker, and a C-terminal domain (CTD), which mediates constitutive dimerization between subunits and often contains an endonuclease active site. Most MutL homologs direct strand-specific DNA mismatch repair by cleaving the error-containing daughter DNA strand. The strand cleavage reaction is poorly understood; however, the structure of the endonuclease active site is consistent with a two- or three-metal ion cleavage mechanism. A motif required for this endonuclease activity is present in the unstructured linker of Mlh1 and is conserved in all eukaryotic Mlh1 proteins, except those from metamonads, which also lack the almost absolutely conserved Mlh1 C-terminal phenylalanine-glutamate-arginine-cysteine (FERC) sequence. We hypothesize that the cysteine in the FERC sequence is autoinhibitory, as it sequesters the active site. We further hypothesize that the evolutionary co-occurrence of the conserved linker motif with the FERC sequence indicates a functional interaction, possibly by linker motif-mediated displacement of the inhibitory cysteine. This role is consistent with available data for interactions between the linker motif with DNA and the CTDs in the vicinity of the active site.
Identifiants
pubmed: 37424007
doi: 10.1002/bies.202300031
pmc: PMC10530380
mid: NIHMS1917753
doi:
Substances chimiques
MutL Proteins
EC 3.6.1.3
Cysteine
K848JZ4886
MutL Protein Homolog 1
EC 3.6.1.3
DNA
9007-49-2
Endonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2300031Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM050006
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023 The Authors. BioEssays published by Wiley Periodicals LLC.
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