Repair of DNA double-strand breaks by mammalian alternative end-joining pathways.

J Biol Chem

From the Departments of Internal Medicine and Molecular Genetics and Microbiology, University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico 87131

Published: July 2018

Alternative end-joining (a-EJ) pathways, which repair DNA double-strand breaks (DSBs), are initiated by end resection that generates 3' single strands. This reaction is shared, at least in part, with homologous recombination but distinguishes a-EJ from the major nonhomologous end-joining pathway. Although the a-EJ pathways make only a minor and poorly understood contribution to DSB repair in nonmalignant cells, there is growing interest in these pathways, as they generate genomic rearrangements that are hallmarks of cancer cells. Here, we review and discuss the current understanding of the mechanisms and regulation of a-EJ pathways, the role of a-EJ in human disease, and the potential utility of a-EJ as a therapeutic target in cancer.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036210PMC
http://dx.doi.org/10.1074/jbc.TM117.000375DOI Listing

Publication Analysis

Top Keywords

a-ej pathways
12
repair dna
8
dna double-strand
8
double-strand breaks
8
alternative end-joining
8
a-ej
6
pathways
5
breaks mammalian
4
mammalian alternative
4
end-joining pathways
4

Similar Publications

High-complexity of DNA double-strand breaks is key for alternative end-joining choice.

Commun Biol

August 2024

Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.

Article Synopsis
  • - The study investigates the alternative non-homologous end-joining (alt-NHEJ) pathway, highlighting its role in contributing to genetic instability due to repairs of complex DNA double-strand breaks (DSBs).
  • - Researchers developed a novel Escherichia coli reporter system to examine the mechanism of alternative end-joining (A-EJ) in response to DSBs created by different types of ionizing radiation.
  • - Findings suggest that the complexity of DSBs influences the choice of A-EJ for repair, with specific molecular patterns and homology levels near the breaks affecting the repair pathway used, increasing the understanding of DNA repair processes.
View Article and Find Full Text PDF

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

Sci Adv

August 2024

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

G-G phase alternative end joining (A-EJ) is a recently defined mutagenic pathway characterized by resected deletion and translocation joints that are predominantly direct and are distinguished from A-EJ in cycling cells that rely much more on microhomology-mediated end joining (MMEJ). Using chemical and genetic approaches, we systematically evaluate potential A-EJ factors and DNA damage response (DDR) genes to support this mechanism by mapping the repair fates of RAG1/2-initiated double-strand breaks in the context of Igκ locus V-J recombination and chromosome translocation. Our findings highlight a polymerase theta-independent Parp1-XRCC1/LigIII axis as central A-EJ components, supported by 53BP1 in the context of an Ataxia-telangiectasia mutated (ATM)-activated DDR.

View Article and Find Full Text PDF

DNA-PKcs suppresses illegitimate chromosome rearrangements.

Nucleic Acids Res

May 2024

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Two DNA repair pathways, non-homologous end joining (NHEJ) and alternative end joining (A-EJ), are involved in V(D)J recombination and chromosome translocation. Previous studies reported distinct repair mechanisms for chromosome translocation, with NHEJ involved in humans and A-EJ in mice predominantly. NHEJ depends on DNA-PKcs, a critical partner in synapsis formation and downstream component activation.

View Article and Find Full Text PDF

Short Double-Stranded DNA (≤40-bp) Affects Repair Pathway Choice.

Int J Mol Sci

July 2023

Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.

To repair ionizing radiation (IR)-induced double strand breaks (DSBs), mammalian cells primarily use canonical non-homologous end-joining (cNHEJ), the homologous recombination (HR) pathway, and the alternative non-homologous end-joining (aEJ) as a backup. These pathways function either compensatively or competitively. High linear energy transfer (LET) compared to low-LET IR kills more cells at the same doses by inhibiting only cNHEJ, but not HR or aEJ.

View Article and Find Full Text PDF

Fanconi anemia-associated chromosomal radial formation is dependent on POLθ-mediated alternative end joining.

Cell Rep

May 2023

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

Activation of the Fanconi anemia (FA) pathway after treatment with mitomycin C (MMC) is essential for preventing chromosome translocations termed "radials." When replication forks stall at MMC-induced interstrand crosslinks (ICLs), the FA pathway is activated to orchestrate ICL unhooking and repair of the DNA break intermediates. However, in FA-deficient cells, how ICL-associated breaks are resolved in a manner that leads to radials is unclear.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!