DNA repair pathways can enable tumour cells to survive DNA damage that is induced by chemotherapeutic treatments; therefore, inhibitors of specific DNA repair pathways might prove efficacious when used in combination with DNA-damaging chemotherapeutic drugs. In addition, alterations in DNA repair pathways that arise during tumour development can make some cancer cells reliant on a reduced set of DNA repair pathways for survival. There is evidence that drugs that inhibit one of these pathways in such tumours could prove useful as single-agent therapies, with the potential advantage that this approach could be selective for tumour cells and have fewer side effects.

/pdf/dna-repair-pathways-as-targets-for-cancer-therapy-lqpcnvg87i.pdf

DNA repair pathways as targets for cancer therapy

Over the past decade, the human identity testing community has settled on a set of core short tandem repeat (STR) loci that are widely used for DNA typing applications. A variety of commercial kits enable robust amplification of these core STR loci. A brief history is presented regarding the selection of core autosomal and Y-chromosomal STR markers. The physical location of each STR locus in the human genome is delineated and allele ranges and variants observed in human populations are summarized as are mutation rates observed from parentage testing. Internet resources for additional information on core STR loci are reviewed. Additional topics are also discussed, including potential linkage of STR loci to genetic disease-causing genes, probabilistic predictions of sample ethnicity, and desirable characteristics for additional STR loci that may be added in the future to the current core loci. These core STR loci, which form the basis for DNA databases worldwide, will continue to play an important role in forensic science for many years to come.

https://www.sjsu.edu/people/steven.lee/courses/JS111FLUOR/s0/Butler2006JFS_coreSTRreview.pdf

Genetics and genomics of core short tandem repeat loci used in human identity testing.

The structure and integrity of telomeres are essential for genome stability. Telomere dysregulation can lead to cell death, cell senescence, or abnormal cell proliferation. The maintenance of telomere repeats in most eukaryotic organisms requires telomerase, which consists of a reverse transcriptase (RT) and an RNA template that dictates the synthesis of the G-rich strand of telomere terminal repeats. Structurally, telomerase reverse transcriptase (TERT) contains unique and variable N- and C-terminal extensions that flank a central RTlike domain. The enzymology of telomerase includes features that are both similar to and distinct from those characteristic of other RTs. Two distinguishing features of TERT are its stable association with the telomerase RNA and its ability to repetitively reverse transcribe the template segment of RNA. Here we discuss TERT structure and function; its regulation by RNA-DNA, TERT-DNA, TERT-RNA, TERT-TERT interactions, and TERT-associated proteins; and the relationship between telomerase enzymology and telomere maintenance.

The structure and function of telomerase reverse transcriptase

The DNA Damage Machinery and Homologous Recombination Pathway Act Consecutively to Protect Human Telomeres

The faithful maintenance of chromosome continuity in human cells during DNA replication and repair is critical for preventing the conversion of normal diploid cells to an oncogenic state The evolution of higher eukaryotic cells endowed them with a large genetic investment in the molecular machinery that ensures chromosome stability In mammalian and other vertebrate cells, the elimination of double-strand breaks with minimal nucleotide sequence change involves the spatiotemporal orchestration of a seemingly endless number of proteins ranging in their action from the nucleotide level to nucleosome organization and chromosome architecture DNA DSBs trigger a myriad of post-translational modifications that alter catalytic activities and the specificity of protein interactions: phosphorylation, acetylation, methylation, ubiquitylation, and SUMOylation, followed by the reversal of these changes as repair is completed "Superfluous" protein recruitment to damage sites, functional redundancy, and alternative pathways ensure that DSB repair is extremely efficient, both quantitatively and qualitatively This review strives to integrate the information about the molecular mechanisms of DSB repair that has emerged over the last two decades with a focus on DSBs produced by the prototype agent ionizing radiation (IR) The exponential growth of molecular studies, heavily driven by RNA knockdown technology, now reveals an outline of how many key protein players in genome stability and cancer biology perform their interwoven tasks, eg ATM, ATR, DNA-PK, Chk1, Chk2, PARP1/2/3, 53BP1, BRCA1, BRCA2, BLM, RAD51, and the MRE11-RAD50-NBS1 complex Thus, the nature of the intricate coordination of repair processes with cell cycle progression is becoming apparent This review also links molecular abnormalities to cellular pathology as much a possible and provides a framework of temporal relationships

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: the molecular choreography.

The protein products of several rad checkpoint genes of Schizosaccharomyces pombe (rad1+, rad3+, rad9+, rad17+, rad26+, and hus1+) play crucial roles in sensing changes in DNA structure, and several function in the maintenance of telomeres. When the mammalian homologue of S. pombe Rad9 was inactivated, increases in chromosome end-to-end associations and frequency of telomere loss were observed. This telomere instability correlated with enhanced S- and G2-phase-specific cell killing, delayed kinetics of γ-H2AX focus appearance and disappearance, and reduced chromosomal repair after ionizing radiation (IR) exposure, suggesting that Rad9 plays a role in cell cycle phase-specific DNA damage repair. Furthermore, mammalian Rad9 interacted with Rad51, and inactivation of mammalian Rad9 also resulted in decreased homologous recombinational (HR) repair, which occurs predominantly in the S and G2 phases of the cell cycle. Together, these findings provide evidence of roles for mammalian Rad9 in telomere stability and HR repair as a mechanism for promoting cell survival after IR exposure.

/pdf/mammalian-rad9-plays-a-role-in-telomere-stability-s-and-g-2-1o7he8uup1.pdf

Mammalian Rad9 Plays a Role in Telomere Stability, S- and G 2 -Phase-Specific Cell Survival, and Homologous Recombinational Repair

https://www.cell.com/trends/genetics/pdf/S0168-9525(03)00135-5.pdf

Telomere maintenance and DNA replication: how closely are these two connected?

ATM/ATR homologs are the central elements of genome surveillance mechanisms in many organisms, including yeasts, flies, and mammals. In Saccharomyces cerevisiae, most checkpoint responses depend on the ATR ortholog Mec1p. The yeast ATM ortholog, Tel1p, so far has been implicated in a specific DNA damage checkpoint during S-phase as well as in telomere homeostasis. In particular, yeast cells lacking only Tel1p harbor short but stable telomeres, while cells lacking both Tel1p and Mec1p are unable to maintain telomeric repeats and senesce. Here, we present the characterization of a new mutation in the TEL1-gene, called tel1-11, which was isolated by virtue of a synthetic lethal interaction at 37°C with a previously described mec1-ts mutation. Interestingly, telomere and checkpoint functions are differentially affected by the mutant protein Tel1-11p. The Tel1p-dependent checkpoint response is undetectable in cells containing Tel1-11p and incubated at 37°C, but basic telomere function is maintained. Further, when the same cells are incubated at 26°C, Tel1-11p confers full proficiency for all telomere functions analyzed, whereas the function for DNA-damage checkpoint activation is clearly affected. The results thus strongly suggest that the different cellular pathways affected by Tel1p do not require the same level of Tel1p activity to be fully functional.

Mikhail Chakhparonian

Papers

Mammalian Rad9 Plays a Role in Telomere Stability, S- and G 2 -Phase-Specific Cell Survival, and Homologous Recombinational Repair

Telomere maintenance and DNA replication: how closely are these two connected?

A mutation in yeast Tel1p that causes differential effects on the DNA damage checkpoint and telomere maintenance