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DNA and Chromosome Aberrations Research

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Research on DNA and chromosome aberrations focuses on cancer genetics and epigenetics. Topics include regulation of gene expression; DNA damage from exposure to chemical, physical, and endogenous agents; mechanisms of DNA damage signaling and DNA repair; and genomic instability and related molecular, cytogenetic, and chromosomal effects during tumor formation and progression to malignancy.

Research in this area is supported and directed by the DNA and Chromosome Aberrations Branch (DCAB).

Gene Regulation and Epigenetics

Gene regulations and epigenetics research focuses on the aberrant expression of cellular genes that regulate normal cell function, which is a hallmark of cancer cells. The regulation of gene expression often involves altering the ability of the DNA to organize with histone proteins into a higher-order chromatin structure that is permissive for gene expression.

Key research areas include:

  • Chemical and structural modifications of DNA and RNA, as well as modification of histones, changes in organization of the cell nucleus, and altered activity of non-coding RNAs that either stimulate or inhibit gene expression
  • Enzymes involved in the methylation and demethylation of DNA and in the methylation, demethylation, acetylation, and deacetylation of histones
  • Chromatin architectural proteins that mediate higher-order chromatin structure or control DNA accessibility and heterochromatin assembly
  • Characterization of major regulatory regions of DNA involved in gene expression and their interacting proteins
  • Identification and role of non-coding RNAs in regulating gene expression and identification of their gene targets
  • Identification, mechanism of action, and downstream effects of families of eukaryotic transcription factors

Emerging research areas include epigenetic changes that drive pediatric solid tumors; the systematic characterization of chemical modifications of RNA (epitranscriptome) as well as the readers, writers, and erasers of these modifications; and the role of epigenetic marks in establishing transgenerational epigenetic inheritance.

Mechanisms of Genomic Instability

Certain chromosomal aberrations are hallmarks of tumor initiation and progression. Genomic instability encompasses a wide spectrum of defects ranging from localized point mutations of one or a few DNA base pairs to large chromosomal rearrangements, such as deletions, amplifications, inversions, translocations, and aneuploidy.

Key research areas include:

  • Mechanisms involved in mitotic chromosome segregation and chromosome imbalance, translocations, and fragile sites
  • Telomere alterations and mechanisms of telomerase function in cancer initiation and progression
  • Chromatin assembly, nuclear architecture, chromosome territories, and chromatin domain structure
  • Genomic instability arising during DNA replication stress
  • Role of oncogenes in promoting genomic instability
  • Role of DNA fragile sites, which are regions of the chromosome that are prone to breakage and are hotspots for translocations
  • Role of nonconventional DNA structures in generating fragile sites

Emerging research areas include understanding the role of DNA repair mechanisms in genomic instability; the roles of telomeres in cell differentiation, cell death, and DNA repair; and the cause and consequences of catastrophic chromosomal events like chromothripsis.

Cancer Genetics

Research in cancer genetics focuses on the identification, mapping, and characterization of genes and chromosomal regions involved in tumor initiation and progression. The identification of driver mutations that promote tumorigenesis by providing a growth advantage to cancer cells is of particular interest.

Key research areas include:

  • Studies of intra-tumoral genetic heterogeneity and clonal evolution
  • Functional genomics, including the role of cancer gene variants and single nucleotide polymorphisms
  • Application of model systems for gene discovery and genetic screens to identify loci that cooperate with known cancer genes
  • Genes activated or repressed by radiation and chemical exposure

An emerging area of interest is the role that chromosome translocations play in driving tumorigenesis and cancer progression.

Mechanisms of DNA Damage and Repair

Cells typically have DNA repair mechanisms by which they can repair damage to a cell when it occurs. Studies on carcinogen-induced and endogenous DNA damage, including altered fidelity of DNA replication and translesion DNA polymerases, as well as DNA repair mechanisms (e.g., nucleotide and base excision, transcription-coupled, recombination, cross-link, and mismatch repair pathways) lead to better understanding of the circumstances under which damaged cells fail to be repaired.

Key research areas include:

  • The repair of DNA lesions and DNA breaks induced by carcinogens, mutagens, reactive oxygen species, chemotherapeutic agents, and ionizing/non-ionizing radiation
  • Lesion-induced conformational changes in DNA and how altered nuclear and chromatin integrity affect DNA repair

An emerging area is the homologous recombination repair of double-strand breaks in replication restart and during replication stress common in cancer cells. An understanding of the underlying mechanisms of DNA repair can be used to design strategies to selectively target cancer cells.

Mechanisms of DNA Damage Signaling

Studies on the mechanisms of DNA damage focus on signaling in both the cytoplasm and mitochondria of normal and transformed human cells, in model eukaryotic systems during different phases of the cell cycle, and in non-dividing indolent states.

Key research areas include:

  • How cells detect DNA lesions
  • DNA lesion, chromosomal damage, and replication stress-induced checkpoints and signal transduction, including activation of DNA damage response (DDR)-induced kinases
  • DNA damage-induced cell death
  • DDR checkpoint failure and mitotic catastrophe

One mechanism that cancer cells use to maintain their cancerous phenotype is compromised repair of chromosome breaks. An emerging research area is the design of therapeutic strategies that target either DNA repair or DNA damage signaling to inhibit pathways that are vital for cancer cells with little effect on non-cancerous cells.

Chemical and Physical Carcinogenesis

An important area of study is the mechanisms by which chemical and physical carcinogens initiate and promote cancer. Carcinogenic agents include chemical mutagens, tobacco smoke, toxins, ultraviolet light, radiation, asbestos, and reactive oxidative species.

Key research areas include:

  • Mechanisms of carcinogenesis by DNA adduct generation or alteration of signaling pathways
  • Formation, detection and metabolism of chemical carcinogens
  • Mechanisms of DNA mutagenesis and characterization of oxidant-induced DNA lesions induced by chemicals, ultraviolet light, ionizing radiation, and endogenous reactive oxygen species
  • Mechanisms of cancer initiation and promotion by ionizing or non-ionizing agents
  • Differential susceptibilities of cells to carcinogens and subsequent progression to cancer
  • Modulation of the inflammatory response by chemical or physical agents

An emerging research area is the toxicity of nontraditional tobacco products like electronic cigarettes and water pipes.

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