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PAXX和MRI在染色体末端连接过程中的不同功能。

Distinct functions of PAXX and MRI during chromosomal end joining.

作者信息

Cisneros-Aguirre Metztli, Lopezcolorado Felicia Wednesday, Ping Xiaoli, Chen Ruby, Stark Jeremy M

机构信息

Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA.

Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA.

出版信息

iScience. 2025 May 22;28(6):112722. doi: 10.1016/j.isci.2025.112722. eCollection 2025 Jun 20.

DOI:10.1016/j.isci.2025.112722
PMID:40546969
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12179622/
Abstract

A key step of canonical-nonhomologous end joining is synapsis of DNA double-strand break (DSB) ends, which appears to be mediated by both the DNA-PKcs dimer and XLF homodimer. We have examined this process by monitoring end joining (EJ) of blunt Cas9 DSBs, focusing on the Ku-binding factors PAXX and MRI. We found that PAXX and/or MRI are dispensable for such EJ. However, PAXX becomes important for blunt DSB EJ with disruption of either DNA-PKcs or XLF, whereas MRI becomes important only with XLF disruption. In contrast, while DNA-PKcs also suppresses short deletion mutations with microhomology, this effect is not magnified with PAXX loss. Finally, XLF loss causes an increase in larger deletions compared to DNA-PKcs inhibition, which is magnified with loss of MRI. We suggest that PAXX promotes DSB end synapsis in a manner that is partially redundant with DNA-PKcs and XLF, whereas MRI is a backup factor for XLF-mediated EJ.

摘要

经典非同源末端连接的一个关键步骤是DNA双链断裂（DSB）末端的联会，这似乎由DNA-PKcs二聚体和XLF同二聚体共同介导。我们通过监测平端Cas9 DSB的末端连接（EJ）来研究这一过程，重点关注Ku结合因子PAXX和MRI。我们发现，PAXX和/或MRI对于此类EJ是可有可无的。然而，当DNA-PKcs或XLF受到破坏时，PAXX对于平端DSB的EJ变得重要，而MRI仅在XLF受到破坏时才变得重要。相比之下，虽然DNA-PKcs也能抑制具有微同源性的短缺失突变，但这种效应不会因PAXX缺失而增强。最后，与DNA-PKcs抑制相比，XLF缺失会导致更大缺失的增加，而MRI缺失会使这种增加更加明显。我们认为，PAXX以一种与DNA-PKcs和XLF部分冗余的方式促进DSB末端联会，而MRI是XLF介导的EJ的备用因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/fcaee6f68b48/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/a00f6cc760a7/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/95257cb32c05/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/035a8ccd3074/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/fb6bc1097d39/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/e36599b1eedd/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/d54b0ce0c34b/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/d09adefdfcf6/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/0663a933ebae/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/fcaee6f68b48/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/a00f6cc760a7/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/95257cb32c05/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/035a8ccd3074/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/fb6bc1097d39/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/e36599b1eedd/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/d54b0ce0c34b/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/d09adefdfcf6/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/0663a933ebae/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38f/12179622/fcaee6f68b48/gr8.jpg

相似文献

[1]
Distinct functions of PAXX and MRI during chromosomal end joining.

iScience. 2025-5-22

[2]
Distinct functions of PAXX and MRI during chromosomal end joining.

bioRxiv. 2024-8-22

[3]
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FEBS Open Bio. 2019-6-12

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[7]
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[8]
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[9]
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引用本文的文献

[1]
53BP1/RIF1 and DNA-PKcs show distinct genetic interactions with diverse chromosomal break repair outcomes.

bioRxiv. 2025-5-11

[2]
Alternative splicing modulates chromatin interactome and phase separation of the RIF1 C-terminal domain.

bioRxiv. 2024-11-1

本文引用的文献

[1]
ATM and 53BP1 regulate alternative end joining-mediated V(D)J recombination.

Sci Adv. 2024-8-2

[2]
Multivalent interactions of the disordered regions of XLF and XRCC4 foster robust cellular NHEJ and drive the formation of ligation-boosting condensates in vitro.

Nat Struct Mol Biol. 2024-11

[3]
DNA-PKcs suppresses illegitimate chromosome rearrangements.

Nucleic Acids Res. 2024-5-22

[4]
Shifted PAMs generate DNA overhangs and enhance SpCas9 post-catalytic complex dissociation.

Nat Struct Mol Biol. 2023-11

[5]
PAXX binding to the NHEJ machinery explains functional redundancy with XLF.

Sci Adv. 2023-6-2

[6]
Cryo-EM visualization of DNA-PKcs structural intermediates in NHEJ.

Sci Adv. 2023-6-2

[7]
Two distinct long-range synaptic complexes promote different aspects of end processing prior to repair of DNA breaks by non-homologous end joining.

Mol Cell. 2023-3-2

[8]
To indel or not to indel: Factors influencing mutagenesis during chromosomal break end joining.

DNA Repair (Amst). 2022-10

[9]
The importance of DNAPKcs for blunt DNA end joining is magnified when XLF is weakened.

Nat Commun. 2022-6-27

[10]
53BP1 regulates heterochromatin through liquid phase separation.

Nat Commun. 2022-1-18

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