MALAT1 is essential for A-NHEJ pathway choice during B cell immunoglobulin class switch recombination

Abstract

Abstract Metastasis-associated lung adenocarcinoma transcript 1(MALAT1) has been found high expressed in multiple cancer type including B cell lymphoma and multiple myeloma. In human cancer murine models, deficiency of MALAT1 reduce the tumor burden and malignancy phynotype. We have identified MALAT1 in alternative-non-homozygous end joining(A-NHEJ) pathway by binding to PARP1 and LIG3 in multiple myeloma cells, two key components of the A-NHEJ protein complex. To investigate requirments for MALAT1 in A-NHEJ pathway, by using MALAT1 deficient mice, we found that the contribution of MALAT1 in the context of AID induced DNA breaks in CSR of B cells in mice. MALAT1 is required for A-NHEJ DNA repair pathway, but not the NHEJ pathway, which is the major DNA repair pathway for CSR. To further prove the hypothesis that MALAT1 promote A-NHEJ pathway in B cells, we have engineered mice that conditionally overexpress MALAT1 in B lymphocytes confers a strong A-NHEJ activity in CSR. More importantly, we also found IgH/c-myc translocations are promoted in MALAT1 B cell specific transgenic mice. Thus, we identified MALAT1 as a critical noncoding RNA in regulating A-NHEJ pathway during CSR.