Genomic Instability in Cancer

Abstract

One of the fundamental challenges facing the cell is to accurately copy its genetic material to daughter cells. When this process goes awry, genomic instability ensues in which genetic alterations ranging from nucleotide changes to chromosomal translocations and aneuploidy occur. Organisms have developed multiple mechanisms that can be classified into two major classes to ensure the fidelity of DNA replication. The first class includes mechanisms that prevent premature initiation of DNA replication and ensure that the genome is fully replicated once and only once during each division cycle. These include cyclin-dependent kinase (CDK)-dependent mechanisms and CDK-independent mechanisms. Although CDK-dependent mechanisms are largely conserved in eukaryotes, higher eukaryotes have evolved additional mechanisms that seem to play a larger role in preventing aberrant DNA replication and genome instability. The second class ensures that cells are able to respond to various cues that continuously threaten the integrity of the genome by initiating DNA-damage-dependent "checkpoints" and coordinating DNA damage repair mechanisms. Defects in the ability to safeguard against aberrant DNA replication and to respond to DNA damage contribute to genomic instability and the development of human malignancy. In this article, we summarize our current knowledge of how genomic instability arises, with a particular emphasis on how the DNA replication process can give rise to such instability.

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

“…Rereplication can be induced experimentally through genetic inactivation of components of the CRL4 CDT2 complex (e.g., through CDT2 depletion or knockdown by siRNA), through CDT1 activation (e.g., by knockdown of geminin, a small protein inhibitor of CDT1), or through the activation of the APC/C CDC20 E3 ligase (e.g., by knockdown of the APC inhibitor EMI1; refs. 11,26). Finally, the discovery that treatment of cancer cells with the neddylation inhibitor pevonedistat (also known as MLN4924) inhibits cancer cell lines and tumors and is associated with significant induction of rereplication demonstrated that rereplication can be induced pharmacologically, and this may have an anticancer activity (27)(28)(29)(30)(31).…”

“…This is mediated primarily through the targeted proteolysis of the replication licensing protein CDT1, the CDK inhibitor p21, and the histone methyltransferase SET8 during the S-phase of the cell cycle (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). CRL4 CDT2 is also activated, and its substrates are degraded, following DNA damage, such as that induced by ionizing radiation (IR), and this is important for PCNA-dependent DNA repair, and for IR-induced early G 2 -M checkpoint (11,26). CRL4 CDT2 -mediated ubiquitylation of CDT1, SET8, and p21 in the S-phase of unperturbed cells prevents reinitiation of DNA replication, a phenomenon termed DNA rereplication.…”

“…CRL4 CDT2 -mediated ubiquitylation of CDT1, SET8, and p21 in the S-phase of unperturbed cells prevents reinitiation of DNA replication, a phenomenon termed DNA rereplication. Rereplication is deleterious to cells and, in some cases, induces cellular senescence and/or apoptosis due to the accumulation of toxic replication intermediates and replication fork stalling (11,26). Rereplication can be induced experimentally through genetic inactivation of components of the CRL4 CDT2 complex (e.g., through CDT2 depletion or knockdown by siRNA), through CDT1 activation (e.g., by knockdown of geminin, a small protein inhibitor of CDT1), or through the activation of the APC/C CDC20 E3 ligase (e.g., by knockdown of the APC inhibitor EMI1; refs.…”

MLH1 -93G>A and I219V polymorphisms are susceptible to increased risk of sporadic colorectal cancer in a Turkish population

“…However, in sporadic cancers, genomic instability is a consequence of DNA damage and alteration in DNA replication due to deregulation of the related genes in addition with impaired DNA repair (Anderson 2001, Negrini et al 2010. Therefore, DNA repair mechanisms play crucial role in cancer prevention through maintaining genomic stability and DNA integrity (Abbas et al 2013). …”

Endocrine Disruptors and Carcinogenesis

“…Endocrine disruptors fall into six categories of chemicals including pesticides (DDT and methoxychlor), fungicides (vinclozolin), herbicides (atrazine), industrial chemicals (PCBs, dioxins), plastics (phthalates, bisphenol A, alkylphenols) and plant hormones (phytoestrogens) [1]. The most important assigned effect for the endocrine disruptors is genomic instability, defined as an increased tendency of the genome to acquire mutations [2]. It occurs when various processes involved in maintaining the genome are dysfunctional or when exposure to carcinogenic chemicals occurs [3].…”