Origin of chromosomal translocations in lymphoid cancer

Abstract

Aberrant fusions between heterologous chromosomes are among the most prevalent cytogenetic abnormalities found in cancer cells. Oncogenic chromosomal translocations provide cells with a proliferative or survival advantage. They may either initiate transformation or be acquired secondarily as a result of genomic instability. Here, we highlight recent advances toward understanding the origin of chromosomal translocations in incipient lymphoid cancers and how tumor-suppressive pathways normally limit the frequency of these aberrant recombination events. Deciphering the mechanisms that mediate chromosomal fusions will open new avenues for developing therapeutic strategies aimed at eliminating lesions that lead to the initiation, maintenance, and progression of cancer.

Figure 1. Misrepair of DNA breaks cause chromosomal translocations[rk4]

Chromosomal translocations require formation of paired double strand DNA breaks (DSBs) on different chromosomes. DSBs can be repaired in cis, or can result in chromosomal translocation by rearrangement between non homologous chromosomes. Depending on the topology of the rearrangement, the translocation can be reciprocal (balanced or unbalanced) or non-reciprocal. The majority of translocations associated with cancer in human lymphoid tumors involve balanced chromosomal translocations, whereas epithelial cancers usually carry complex nonreciprocal translocations.

Figure 2. Antigen diversification reactions in lymphocytes

Lymphocyte antigen receptor diversity is established in developing lymphocytes by V(D)J recombination. Recombinase-activating genes 1 and 2 (RAG1 and RAG2), are transesterases that introduce double strand breaks (DSBs) at recombination signal sequences (shown in triangles) that flank V, D, and J gene segments. These DSBs are repaired by the NHEJ pathway. Mature B cells undergo two additional diversification reactions called somatic hypermutation and class switch recombination. These two processes are initiated by AID, a single strand DNA deaminase that mutates cytidine residues to uracyl. Cytdine deamination at V regions leads to somatic mutation whereas the same alteration in switch (S) regions causes class switching. AID generated mismatches in DNA are processed by base-exision repair (BER), mismatch repair (MMR), and error prone polymerases to generate mutations during somatic hypermutation. These lesions can also be converted to a DSB, an obligate intermediate during class switch recombination. These DSBs are detected and processed by foci forming factors, nonhomologous end joining (NHEJ) and alternative end joining [rk5](A-NHEJ). Accurate repair of DSBs by foci forming factors and NHEJ is necessary to prevent chromosomal translocation. Most lymphoid cancers carry chromosomal translocations that involve RAG1/2 or AID target genes. Eμ, intronic enhancer; 3′E, 3′ enhancer.

Figure 3. Repair of DNA double strand breaks

Two major mechanisms that repair double strand breaks (DSBs) include homologous recombination (HR) and non-homologous end joining (NHEJ). HR repairs DSBs by using an intact copy of the broken chromosome as template and is restricted in S and G2 phases of the cell cycle. HR is initiated by 5′-3′ resection of DSBs to form single stranded DNA. A complex of BRCA1, MRN, and CtIP is required for DSB resection. After ssDNA generation, a RAD51 nucleoprotein filament facilitated by BRCA2 is formed that initiates strand invasion of the intact sister chromatid. After DNA synthesis, the ends are eventually rejoined to yield the intact products. During NHEJ, DNA ends are recognized by the Ku70/80 heterodimer and DNA-PKcs. They are then processed by a complex consisting of Artemeis, XLF, XRCC4 and Lig4. Alternative NHEJ (A-NHEJ) pathways may also function as a backup to classical NHEJ. NHEJ and HR components are caretakers that maintain genomic stability by suppressing chromosomal translocations.

Figure 4. Evolution of a DNA repair focus

A focus represents large-scale accumulation of factors in the chromatin flanking a double strand break (DSB). MRN recognizes the DSBs, and recruits and activates ATM, a kinase that phosphorylates numerous factors at DSBs including histone H2AX and MDC1. Two E3 ubiquitin ligases RNF8 and RNF168 (coupled with the E2 enzyme UBC13) promote local chromatin ubiquitination, including ubiquitination of H2A histones. RNF8 and RNF168 promote chromatin retention of 53BP1 and Brca1. Modifications of histones may allow exposure of partially occluded histone methyl marks, which facilitates retention of 53BP1. The complex of Rap80/Brca1 interacts directly with ubiquitinated histones. Foci formation stabilizes complexes on chromatin, but is not required for their initial recruitment to damaged sites.