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Nonhomologous DNA End Joining (NHEJ) and Chromosomal Translocations in Humans

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Genome Stability and Human Diseases

Part of the book series: Subcellular Biochemistry ((SCBI,volume 50))

Abstract

Double-strand breaks (DSBs) arise in dividing cells about ten times per cell per day. Causes include replication across a nick, free radicals of oxidative metabolism, ionizing radiation, and inadvertent action by enzymes of DNA metabolism (such as failures of type II topoisomerases or cleavage by recombinases at off-target sites). There are two major double-strand break repair pathways. Homologous recombination (HR) can repair double-strand breaks, but only during S phase and typically only if there are hundreds of base pairs of homology. The more commonly used pathway is nonhomologous DNA end joining, abbreviated NHEJ. NHEJ can repair a DSB at any time during the cell cycle and does not require any homology, although a few nucleotides of terminal microhomology are often utilized by the NHEJ enzymes, if present. The proteins and enzymes of NHEJ include Ku, DNA-PKcs, Artemis, DNA polymerase μ (Pol μ), DNA polymerase λ (Pol λ), XLF (also called Cernunnos), XRCC4, and DNA ligase IV. These enzymes constitute what some call the classical NHEJ pathway, and in wild type cells, the vast majority of joining events appear to proceed using these components. NHEJ is present in many prokaryotes, as well as all eukaryotes, and very similar mechanistic flexibility evolved both convergently and divergently. When two double-strand breaks occur on different chromosomes, then the rejoining is almost always done by NHEJ. The causes of DSBs in lymphomas most often involve the RAG or AID enzymes that function in the specialized processes of antigen receptor gene rearrangement.

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Abbreviations

AID:

activation-induced deaminase.

CpG:

the DNA sequence where the dinucleotide is 5′ CG 3′. These sites are distinctive because the C in such a sequence is methylated at the 5 position of the cytosine.

CSR:

class switch recombination, the process by which the Ig heavy chain isotype is changed from IgM to IgG, A or E by DNA recombination using switch regions. This process requires AID.

DNA-PKcs:

this is a serine/threonine protein kinase that is stimulated by free DNA ends. It phosphorylates itself and Artemis, the nuclease of NHEJ.

HR:

homologous recombination.

icr:

intermediate cluster region of the bcl-2 gene.

MBR:

major break point cluster region of the bcl-2 gene.

mcr:

minor break point cluster region of the bcl-2 gene.

MLL:

mixed-lineage lymphoma.

MTC:

major translocation cluster of the bcl-1 gene.

NHEJ:

nonhomologous DNA end joining.

PCNA:

proliferating cell nuclear antigen.

Pol λ:

DNA polymerase λ.

Pol μ:

DNA polymerase μ.

RAG:

recombination activating gene.

RSS:

recombination signal sequence. This is the sequence at which the RAG1:RAG2:HMGB1 complex, also called the RAG complex, binds in a sequence-specific manner to initiate the double-strand breaks that begin the V(D)J recombination process. The RSS has two components: CACAGTG, called the heptamer, and ACAAAAACC, called the nonamer, and the hetamer and nonamer are separated by either 12 nonconserved base pairs (then designated as a 12-RSS) or 23 base pairs (then designated as a 23-RSS). The RAG complex cuts 5′ to the first C of the CACAGTG.

SHM:

somatic hypermutation, which is a process of point mutagenesis at the Ig genes, primarily in the assembled VJ or VDJ exons, which encode the variable domain exon of the light and heavy chains, respectively. SHM, like CSR, requires AID.

Switch regions:

repetitive zones upstream of the constant domains exons for the heavy chains genes, Igγ, Igα, and Igɛ.

V(D)J:

refers to the variable, diversity or joining segment (subexons) that must be assembled during the process of V(D)J recombination so that a complete variable domain exon can be generated at the immunoglobulin (Ig) and T-cell receptor (TCR) loci.

XLF:

XRCC4-like factor (also called Cernunnos). This protein is part of the XLF:XRCC4:DNA ligase IV complex.

XRCC4:

XRCC4 cross-complementation group 4. This protein is part of the XLF:XRCC4:DNA ligase IV complex.

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Authors and Affiliations

  1. USC Norris Comprehensive Cancer Center, Los Angeles, CA, 90089-9176, USA

    Michael R. Lieber, Jiafeng Gu, Haihui Lu, Noriko Shimazaki & Albert G. Tsai

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  2. Jiafeng Gu
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Correspondence to Michael R. Lieber .

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    Heinz-Peter Nasheuer

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Lieber, M.R., Gu, J., Lu, H., Shimazaki, N., Tsai, A.G. (2010). Nonhomologous DNA End Joining (NHEJ) and Chromosomal Translocations in Humans. In: Nasheuer, HP. (eds) Genome Stability and Human Diseases. Subcellular Biochemistry, vol 50. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3471-7_14

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