Dysfunctional homologous recombination mediates genomic instability and progression in myeloma

Abstract

A prominent feature of most if not all cancers is a striking genetic instability, leading to ongoing accrual of mutational changes, some of which underlie tumor progression, including acquisition of invasiveness, drug resistance, and metastasis. Thus, the molecular basis for the generation of this genetic diversity in cancer cells has important implications in understanding cancer progression. Here we report that homologous recombination (HR) activity is elevated in multiple myeloma (MM) cells and leads to an increased rate of mutation and progressive accumulation of genetic variation over time. We demonstrate that the inhibition of HR activity in MM cells by small inhibitory RNA (siRNAs) targeting recombinase leads to significant reduction in the acquisition of new genetic changes in the ge- IntroductionGenetic changes observed at the chromosomal level or at the nucleotide sequence level are associated with the development and progression of malignant phenotypes. Although some specific cancers are associated with and attributed to specific cytogenetic and molecular aberrations, for example, chronic myelogenous leukemia or acute promyelocytic leukemia, the majority of cancers display a complex spectra of diverse genetic alterations apparent at diagnosis and acquire additional changes with progression of the disease. 1 Because the large-scale chromosomal alterations that arise frequently in cancer cells occur infrequently in normal cells, [2][3][4] it implies that the control mechanisms that maintain the integrity of chromosomes in normal cells are disrupted in cancer cells.A variety of intrinsic or extrinsic chemical as well as physical factors damage DNA in living organisms which, if not repaired, can lead to mutations and cellular transformation. The best known machinery involved in repairing potentially lethal DNA damage, especially double-strand breaks, is genetic recombination. 5 In fact the repair of DNA lesions may account for majority of the recombination occurring in mitosis. 6 Recombination plays an important role in maintaining the genetic integrity of a cell, including DNA repair 7 and proper segregation of chromosomes in meiosis. 8 In the normal cellular environment, recombination-associated proteins are highly regulated, precise, and exhibit considerable specificity for DNA sequences, which have either an extensive homology or a characteristic signal sequence. However, with its significant ability to modify DNA, if dysregulated, it can lead to genomic instability. Recombination can be induced by several chemicals, radiation, and oncogenic viruses. [9][10][11][12][13][14] The induction or overexpression of a recombination pathway may result in DNA rearrangements, leading to oncogene activation 15 and/or the loss of hemizygous functional alleles of tumor suppressor genes.Aberrant or dysregulated recombination has been implicated in chromosome translocation, 9,16,17 gene amplification, 18 and telomere maintenance 19 and may therefore underlie the chromosomal aberrations observed with high frequency i...

Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data

“…45 Increased homologous recombination activity and elevated expression of HR-related genes, including RAD51, has been suggested to mediate DNA instability and progression of MM. 46 FABP5 is expressed in various malignancies; it is a major target of the proto-oncogene c-MYC 47 and is involved in resistance of solid tumor cells to retinoic acid treatment.…”

Art Materials Can Be Dangerous! How Can You Reduce Your Risk?

“…We have also found that if you treat cancer cells with nickel that further increases their HR and increases their ability to develop resistance to cancer treatment [2].…”

“…More importantly, changes in DNA can also enable a cancer cell to become more aggressive and to resist cancer treatment. Data from our laboratory show that a major DNA repair system known as "homologous recombination" (HR) is overactive in some cancers [2]. Over activation of HR makes it defective and less precise, so instead of just fixing the damaged DNA it also gets involved in making unnecessary rearrangements…”

Telomeres and Lifestyle Choices

“…Telomerases are reactivated in most cancers and immortalized cells. However, a subset of cancer/ immortalized cells lack telomerase activity and maintain telomere length by alternative mechanisms, probably involving genetic (homologous) recombination [Dunham et al, 2000], which is elevated in most immortal/cancer cell lines [Shammas et al, 2009].…”