BackgroundAlthough depression is known to affect millions of people worldwide, individuals seeking aid from qualified health care professionals are faced with a number of barriers to treatment including a lack of treatment resources, limited number of qualified service providers, stigma associated with diagnosis and treatment, prolonged wait times, cost, and barriers to accessibility such as transportation and clinic locations. The delivery of depression interventions through the Internet may provide a practical solution to addressing some of these barriers.ObjectiveThe purpose of this scoping review was to answer the following questions: (1) What Web-delivered programs are currently available that offer an interactive treatment component for depression?, (2) What are the contents, accessibility, and usability of each identified program?, and (3) What tools, supports, and research evidence are available for each identified program?MethodsUsing the popular search engines Google, Yahoo, and Bing (Canadian platforms), two reviewers independently searched for interactive Web-based interventions targeting the treatment of depression. The Beacon website, an information portal for online health applications, was also consulted. For each identified program, accessibility, usability, tools, support, and research evidence were evaluated and programs were categorized as evidence-based versus non-evidence-based if they had been the subject of at least one randomized controlled trial. Programs were scored using a 28-point rating system, and evidence- versus non-evidence-based programs were compared and contrasted. Although this review included all programs meeting exclusion and inclusion criteria found using the described search method, only English language Web-delivered depression programs were awarded an evaluation score.ResultsThe review identified 32 programs meeting inclusion criteria. There was a great deal of variability among the programs captured in this evaluation. Many of the programs were developed for general adolescent or adult audiences, with few (n=2) focusing on special populations (eg, military personnel, older adults). Cognitive behavioral therapy was the most common therapeutic approach used in the programs described. Program interactive components included mood assessments and supplementary homework sheets such as activity planning and goal setting. Only 12 of the programs had published evidence in support of their efficacy and treatment of depressive symptoms.ConclusionsThere are a number of interactive depression interventions available through the Internet. Recommendations for future programs, or the adaptation of existing programs include offering a greater selection of alternative languages, removing registration restrictions, free trial periods for programs requiring user fees, and amending programs to meet the needs of special populations (eg, those with cognitive and/or visual impairments). Furthermore, discussion of specific and relevant topics to the target audience while also enhancing overall...

Failing to repair DNA double-strand breaks by either nonhomologous end joining (NHEJ) or homologous recombination (HR) poses a threat to genome integrity, and may have roles in the onset of aging and age-related diseases. Recent work indicates an age-related decrease of NHEJ efficiency in mouse models, but whether NHEJ and HR change with age in humans and the underlying mechanisms of such a change remain uncharacterized. Here, using 50 eyelid fibroblast cell lines isolated from healthy donors at the age of 16-75 years, we demonstrate that the efficiency and fidelity of NHEJ, and the efficiency of HR decline with age, leading to increased IR sensitivity in cells isolated from old donors. Mechanistic analysis suggests that decreased expression of XRCC4, Lig4 and Lig3 drives the observed, age-associated decline of NHEJ efficiency and fidelity. Restoration of XRCC4 and Lig4 significantly promotes the fidelity and efficiency of NHEJ in aged fibroblasts. In contrast, essential HR-related factors, such as Rad51, do not change in expression level with age, but Rad51 exhibits a slow kinetics of recruitment to DNA damage sites in aged fibroblasts. Further rescue experiments indicate that restoration of XRCC4 and Lig4 may suppress the onset of stress-induced premature cellular senescence, suggesting that improving NHEJ efficiency and fidelity by targeting the NHEJ pathway holds great potential to delay aging and mitigate aging-related pathologies. Cell Death and Differentiation (2016) 23, 1765-1777; doi:10.1038/cdd.2016.65; published online 8 July 2016Aging in mammals is a complex biological process, characterized by several major hallmarks.1,2 Of all the features associated with aging, a gradual destabilization of genome integrity is perhaps the most fundamental as increased genomic instability may lead to other age-associated phenotypes such as cellular senescence and stem cell exhaustion. Indeed, for the past several decades, numerous studies have indicated that DNA mutations and chromosomal rearrangements gradually accumulate with age.3-6 Of all types of DNA lesions, which may contribute to the gradual loss of genetic information during aging, DNA double-strand breaks (DSBs) are the most hazardous to cells as unrepaired or inappropriately repaired DSBs can cause insertions, deletions and chromosomal rearrangements. Using different analysis approaches, several studies have demonstrated that aging is often associated with the accumulation of DNA DSBs in various organs and tissues in mammals such as mice and humans. [7][8][9][10][11] Moreover, a recent study provides direct evidence that an induction of DNA DSBs in genomes causes aging in mouse livers.12 However, why DNA DSBs accumulate with age remains an open question. A number of studies indicate that it may be a consequence of a progressing imbalance between DNA damage and the efficiency of the molecular machinery that catalyzes DNA repair. 7,9,11 Two major pathways, nonhomologous end joining (NHEJ) and homologous recombination (HR) evolved to repair DNA DSBs. NHEJ is...

The NAD+-dependent deacetylase and mono-ADP-ribosyl transferase SIRT6 stabilizes the genome by promoting DNA double strand break repair, thereby acting as a tumor suppressor. However, whether SIRT6 regulates nucleotide excision repair (NER) remains unknown. Here, we showed that SIRT6 was recruited to sites of UV-induced DNA damage and stimulated the repair of UV-induced DNA damage. Mechanistic studies further indicated that SIRT6 interacted with DDB2, the major sensor initiating global genome NER (GG-NER), and that the interaction was enhanced upon UV irradiation. SIRT6 deacetylated DDB2 at two lysine residues, K35 and K77, upon UV stress and then promoted DDB2 ubiquitination and segregation from chromatin, thereby facilitating downstream signaling. In addition, we characterized several SIRT6 mutations derived from melanoma patients. These SIRT6 mutants ablated the stimulatory effect of SIRT6 on NER and destabilized the genome due to (i) partial loss of enzymatic activity (P27S or H50Y), (ii) a nonsense mutation (R150*) or (iii) high turnover rates (G134W). Overall, we demonstrate that SIRT6 promotes NER by deacetylating DDB2, thereby preventing the onset of melanomagenesis.

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Understanding differences in DNA double-strand break (DSB) repair between tumor and normal tissues would provide a rationale for developing DNA repair-targeted cancer therapy. Here, using knock-in mouse models for measuring the efficiency of two DSB repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ), we demonstrated that both pathways are up-regulated in hepatocellular carcinoma (HCC) compared with adjacent normal tissues due to altered expression of DNA repair factors, including PARP1 and DNA-PKcs. Surprisingly, inhibiting PARP1 with olaparib abrogated HR repair in HCC. Mechanistically, inhibiting PARP1 suppressed the clearance of nucleosomes at DNA damage sites by blocking the recruitment of ALC1 to DSB sites, thereby inhibiting RPA2 and RAD51 recruitment. Importantly, combining olaparib with NU7441, a DNA-PKcs inhibitor that blocks NHEJ in HCC, synergistically suppressed HCC growth in both mice and HCC patient-derived-xenograft models. Our results suggest the combined inhibition of both HR and NHEJ as a potential therapy for HCC.