Tissue specificity of DNA damage response and tumorigenesis

Abstract

The genome of cells is constantly challenged by DNA damages from endogenous metabolism and environmental agents. These damages could potentially lead to genomic instability and thus to tumorigenesis. To cope with the threats, cells have evolved an intricate network, namely DNA damage response (DDR) system that senses and deals with the lesions of DNA. Although the DDR operates by relatively uniform principles, different tissues give rise to distinct types of DNA damages combined with high diversity of microenvironments across tissues. In this review, we discuss recent findings on specific DNA damage among different tissues as well as the main DNA repair way in corresponding microenvironments, highlighting tissue specificity of DDR and tumorigenesis. We hope the current review will provide further insights into molecular process of tumorigenesis and generate new strategies for cancer treatment.

Diagnostic, Prognostic, and Immunological Roles of HELLS in Pan-Cancer: A Bioinformatics Analysis

“…In addition, HELLS catalyzes the transfer of macroH2A into mononucleosomes reconstituted by normal core histones in an ATP-dependent manner, therefore shielding nascent DNA from degradation and preserving the chromatin environment at replication forks ( 53 – 55 ). However, the damage is tissue-specific; although DDR operates relatively uniformly, DDR activation can vary across tissue microenvironments, which can lead to tissue-specific tumourigenesis ( 56 ). Thus, HELLS is a protective factor in some cancers but a risk factor in others.…”

RNA Targeting in Acute Myeloid Leukemia

“…The mechanism(s) responsible for the variable incorporation of AzC into DNA versus RNA are currently unknown, but they are likely related to cell-type-specific differences in Pol α-primase complex "stress" and the associated DNA damage response signaling pathways toward programmed cell death or repair. 47 To date, AML subtyping efforts based on DNA mutations, duplications, or translocations have provided two specific classifications of FDA-approved treatment options for ∼35% of AML cases according to PML-RARA translocation 2 or FLT-3 mutation. 3 Ongoing clinical trials are evaluating other treatment-relevant biomarkers, such as NPM1, DNMT3A, and MLL-rearranged leukemias, 34 but the exceptionally high heterogeneity of AML makes any realization of an ideal "onebiomarker, one-treatment" paradigm unlikely.…”

“…This variability reflects the exceptionally high heterogeneity of AML at the molecular-cellular level, and it potentially contributes to the overall low cure rate of this disease (∼30% of cases). , In primary AML samples taken from different patients, RNA over DNA targeting of AzC positively correlated with more favorable outcomes of AML patients receiving curative chemotherapy with ara-C ( p = 0.0555, Figure ). The mechanism(s) responsible for the variable incorporation of AzC into DNA versus RNA are currently unknown, but they are likely related to cell-type-specific differences in Pol α-primase complex “stress” and the associated DNA damage response signaling pathways toward programmed cell death or repair …”

Anti-tumor pharmacology of natural products targeting mitosis

“…DNA damage evokes responses by multiple repair mechanisms and signaling pathways. The DNA damage response (DDR) involves various intra- and inter-cellular signaling events and enzymatic activities that lead to cell-cycle arrest, regulation of DNA replication, and DNA damage repair 82 . Because genomic instability is a pervasive characteristic of tumor cells, DDR defects can serve as therapeutic targets.…”