Endonuclease activities of MutLα and its homologs in DNA mismatch repair

Kadyrova, Lyudmila Y.; Kadyrov, Farid A.

doi:10.1016/j.dnarep.2015.11.023

Cited by 59 publications

(58 citation statements)

References 153 publications

(263 reference statements)

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“…5Bc). A second model posits that assembly of the MutL␣ complex is an early event and that, once formed, the complex slides along DNA and contacts mismatch-activated MutS␣, whereupon the MutL␣ endonuclease activity is activated (54). The key difference is that MutL␣ can independently slide along the DNA contour in the second model.…”

Section: Discussionmentioning

confidence: 99%

MBD4 Facilitates Immunoglobulin Class Switch Recombination

Grigera

Wuerffel

Kenter

2017

Molecular and Cellular Biology

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Immunoglobulin heavy chain class switch recombination (CSR) requires targeted formation of DNA double-strand breaks (DSBs) in repetitive switch region elements followed by ligation between distal breaks. The introduction of DSBs is initiated by activation-induced cytidine deaminase (AID) and requires base excision repair (BER) and mismatch repair (MMR). The BER enzyme methyl-CpG binding domain protein 4 (MBD4) has been linked to the MMR pathway through its interaction with MutL homologue 1 (MLH1). We find that when Mbd4 exons 6 to 8 are deleted in a switching B cell line, DSB formation is severely reduced and CSR frequency is impaired. Impaired CSR can be rescued by ectopic expression of Mbd4. Mbd4 deficiency yields a deficit in DNA end processing similar to that found in MutS homologue 2 (Msh2)-and Mlh1-deficient B cells. We demonstrate that microhomology-rich S-S junctions are enriched in cells in which Mbd4 is deleted. Our studies suggest that Mbd4 is a component of MMR-directed DNA end processing.

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Section: Discussionmentioning

confidence: 99%

MBD4 Facilitates Immunoglobulin Class Switch Recombination

Grigera

Wuerffel

Kenter

2017

Molecular and Cellular Biology

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“…Crystallographic analyses on the C-terminal domain (CTD) of eukaryotic and bacterial MutL endonuclease have shown that the domain is composed of regulatory and dimerization subdomains (11, 26 -28). The dimerization subdomain contains the metal-binding site essential for the endonuclease activity (29), in which two zinc ions are coordinated by the residues from highly conserved motifs: DQHAX 2 EX 4 E, ACR, and CPHGRP (11,15,26,30). These motifs are conserved in MutL from the majority of organisms except for limited species in ␥-proteobacteria (12, 15, 16, 19 -21, 31).…”

Section: Dna Mismatch Repair (Mmr)mentioning

confidence: 99%

Structural Features and Functional Dependency on β-Clamp Define Distinct Subfamilies of Bacterial Mismatch Repair Endonuclease MutL

Fukui

Baba

Kumasaka

et al. 2016

Journal of Biological Chemistry

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In early reactions of DNA mismatch repair, MutS recognizes mismatched bases and activates MutL endonuclease to incise the error-containing strand of the duplex. DNA sliding clamp is responsible for directing the MutL-dependent nicking to the newly synthesized/error-containing strand. In Bacillus subtilis MutL, the ␤-clamp-interacting motif (␤ motif) of the C-terminal domain (CTD) is essential for both in vitro direct interaction with ␤-clamp and in vivo repair activity. A large cluster of negatively charged residues on the B. subtilis MutL CTD prevents nonspecific DNA binding until ␤ clamp interaction neutralizes the negative charge. We found that there are some bacterial phyla whose MutL endonucleases lack the ␤ motif. For example, the region corresponding to the ␤ motif is completely missing in Aquifex aeolicus MutL, and critical amino acid residues in the ␤ motif are not conserved in Thermus thermophilus MutL. We then revealed the 1.35 Å-resolution crystal structure of A. aeolicus MutL CTD, which lacks the ␤ motif but retains the metalbinding site for the endonuclease activity. Importantly, there was no negatively charged cluster on its surface. It was confirmed that CTDs of ␤ motif-lacking MutLs, A. aeolicus MutL and T. thermophilus MutL, efficiently incise DNA even in the absence of ␤-clamp and that ␤-clamp shows no detectable enhancing effect on their activity. In contrast, CTD of Streptococcus mutans, a ␤ motif-containing MutL, required ␤-clamp for the digestion of DNA. We propose that MutL endonucleases are divided into three subfamilies on the basis of their structural features and dependence on ␤-clamp.

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“…The multifunctional MMR system plays a major role in maintaining genome integrity in bacteria and eukaryotes (1)(2)(3)(5)(6)(7)(8). The genetic stability engendered by the MMR system is required for the suppression of both sporadic and inherited cancers in humans (4).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic stabilization provided by the MMR system suppresses both sporadic and inherited cancers (4). The MMR system has multiple functions that are involved in the genome maintenance (1)(2)(3)(5)(6)(7)(8). Among these functions MMR is the strongest contributor to the suppression of spontaneous mutation rates.…”

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confidence: 99%

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DNA Mismatch Repair Interacts with CAF-1- and ASF1A-H3-H4-dependent Histone (H3-H4)2 Tetramer Deposition

Blanko¹,

Kadyrova

Kadyrov

2016

Journal of Biological Chemistry

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DNA mismatch repair (MMR) is required for the maintenance of genome stability and protection of humans from several types of cancer. Human MMR occurs in the chromatin environment, but little is known about the interactions between MMR and the chromatin environment. Previous research has suggested that MMR coincides with replication-coupled assembly of the newly synthesized DNA into nucleosomes. The first step in replication-coupled nucleosome assembly is CAF-1-dependent histone (H3-H4) 2 tetramer deposition, a process that involves ASF1A-H3-H4 complex. In this work we used reconstituted human systems to investigate interactions between MMR and CAF-1-and ASF1A-H3-H4-dependent histone (H3-H4) 2 tetramer deposition. We have found that MutS␣ inhibits CAF-1-and ASF1A-H3-H4-dependent packaging of a DNA mismatch into a tetrasome. This finding supports the idea that MMR occurs before the DNA mismatch is packaged into the tetrasome. Our experiments have also revealed that CAF-1-and ASF1A-H3-H4-dependent deposition of the histone (H3-H4) 2 tetramers does not interfere with MMR reactions. In addition, we have established that unnecessary degradation of the discontinuous strand that takes place in both DNA polymerase ␦ (Pol ␦)-and DNA polymerase ⑀ (Pol ⑀)-dependent MMR reactions is suppressed by CAF-1-and ASF1A-H3-H4-dependent deposition of the histone (H3-H4) 2 tetramers. These data suggest that CAF-1-and ASF1A-H3-H4-dependent deposition of the histone (H3-H4) 2 tetramers is compatible with MMR and protects the discontinuous daughter strand from unnecessary degradation by MMR machinery.

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Endonuclease activities of MutLα and its homologs in DNA mismatch repair

Cited by 59 publications

References 153 publications

MBD4 Facilitates Immunoglobulin Class Switch Recombination

MBD4 Facilitates Immunoglobulin Class Switch Recombination

Structural Features and Functional Dependency on β-Clamp Define Distinct Subfamilies of Bacterial Mismatch Repair Endonuclease MutL

DNA Mismatch Repair Interacts with CAF-1- and ASF1A-H3-H4-dependent Histone (H3-H4)2 Tetramer Deposition

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