Understanding DNA Damage Response and DNA Repair in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance to therapies. Damaged DNA rarely induces an apoptotic response, given the presence of ataxia-telangiectasia mutated (ATM) loss-of-function or mutations, as well as deletions, mutations, or downregulation of tumor protein p53 (TP53) and tumor protein p73 (TP73). Moreover, DNA repair mechanisms are either hyperactive or defective to allow for rapid correction of the damage or permissive survival. Medications used to treat patients with MM can induce DNA damage, by either direct effects (mono-adducts induced by melphalan), or as a result of reactive oxygen species (ROS) production by proteasome inhibitors such as bortezomib. In this review, we will describe the mechanisms of DDR and DNA repair in normal tissues, the contribution of these pathways to MM disease progression and other phenotypes, and the potential therapeutic opportunities for patients with MM.

Aluminium phthalocyanine-mediated photodynamic therapy induces ATM-related DNA damage response and apoptosis in human oesophageal cancer cells

“…Moreover, another study also showed that aluminium phthalocyanine tetra sulfonate (AlPcS 4 )-mediated PDT induced DNA damage in laryngeal cancer ( 35 ). The upregulation of ATM in response to DSB in our study is consistent with established evidence where ATM-mediated repair is believed to be the main mechanism in the DDR pathway to mend DSB lesions ( 33 , 48 ). Furthermore, ATM functions in the regulation of cell cycle checkpoints following cellular stress, especially at the G0/G1, S, and G2/M cell cycle arrest ( 33 , 49 ).…”

Escape from Original Home: Do Metastatic Cells Stay Dormant or Destructive?

“…In the clonal evolution of plasma dyscrasia, genetic heterogeneity of selective clones undergoing primary genetic events such as hyperdiploid and chromosomal abnormality results in clonal expansion of plasma cells, which is called gammopathy of undermined significance (MGUS) or smouldering multiple myeloma which are pre-malignant conditions. Secondary genetic events such as MYC rearrangement, TP53 mutation, or DNA repair alteration results in malignant condition (multiple myeloma) (Petrilla, 2023). By studying ITH during lateral growth and downward growth (invasion) of tumour evolution, the hierarchy of ITH was seen as early and late branching subclones along the phylogenetic tree.…”

Deciphering BRCAness Phenotype in Cancer: A Graph Convolutional Neural Network Approach with Layer-wise Relevance Propagation Analysis

“…Furthermore, the identification of 30 genes directly tied to cancer processes within the top GLRP genes underscores the immediate role these genes play in tumorigenesis and BRCAness-specific pathways. Among these, the inclusion of pivotal genes like TP53 and MYC, integral to cell growth and genomic integrity, indicates their direct contribution to the BRCAness phenotype (Li et al, 2012;Carey et al, 2018;Petrilla et al, 2023). This connection offers insights into tumor behavior, response to treatment, and prognosis, painting a comprehensive picture of the genetic landscape pivotal to BRCAness and its underlying mechanisms.…”