Viral manipulation of DNA repair and cell cycle checkpoints

Recognition and repair of DNA damage is critical for maintaining genomic integrity and suppressing tumorigenesis. In eukaryotic cells, the sensing and repair of DNA damage are coordinated with cell cycle progression and checkpoints, in order to prevent the propagation of damaged DNA. The carefully maintained cellular response to DNA damage is challenged by viruses, which produce a large amount of exogenous DNA during infection. Viruses also express proteins that perturb cellular DNA repair and cell cycle pathways, promoting tumorigenesis in their quest for cellular domination. This review presents an overview of strategies employed by viruses to manipulate DNA damage responses and cell cycle checkpoints as they commandeer the cell to maximize their own viral replication. Studies of viruses have identified key cellular regulators and revealed insights into molecular mechanisms governing DNA repair, cell cycle checkpoints, and transformation.     

Emerging role of sirtuins on tumorigenesis: possible link between aging and cancer

Aging is the strongest risk factor for cancer development, suggesting that molecular crosstalks between aging and tumorigenesis exist in many cellular pathways. Recently, Sirtuins (Sirt1-7), the mammalian homologues of aging-related sir2α in yeast, have been shown to modulate several major cellular pathways, such as DNA repair, inflammation, metabolism, cell death, and proliferation in response to diverse stresses, and may serve as a possible molecular link between aging and tumorignenesis. In addition, growing evidence suggests that sirtuins are directly implicated in the development of cancer, and they can act as either a tumor suppressor or promoter, depending on the cellular context and tumor types. While the functions of Sirt1 in tumorigenesis have been reported and reviewed in many studies, the connection between sirtuins 2-7 and the development of cancer is less established. Thus, this review will present the recent updates on the emerging roles of Sirt2-7 members in carcinogenesis. [BMB Reports 2013; 46(9): 429-438]     

Conserved metabolic regulatory functions of sirtuins

Silent information regulator 2 (Sir2) proteins, or sirtuins, are protein deacetylases/mono-ADP-ribosyltransferases found in organisms ranging from bacteria to humans. Their dependence on nicotinamide adenine dinucleotide (NAD+) links their activity to cellular metabolic status. In bacteria, the sirtuin CobB regulates the metabolic enzyme acetyl-coenzyme A (acetyl-CoA) synthetase. The earliest function of sirtuins therefore may have been regulation of cellular metabolism in response to nutrient availability. Recent findings support the idea that sirtuins play a pivotal role in metabolic control in higher organisms, including mammals. This review surveys evidence for an emerging role of sirtuins as regulators of metabolism in mammals.     

Sirtuins: not only animal proteins

Sirtuins are proteins belonging to the group of NADH-dependent deacetylase and mono-ADP-ribosyltransferase enzymes. Sirtuins have been discovered for the first time in yeasts, subsequent studies have shown their presence in bacteria, plants and animals. These enzymes are frequently called longevity enzymes due to the fact that they are part of genetic apparatus involved in aging control. In animals, sirtuins are key regulators of cell defense in response to stress caused by many metabolic processes; they are also involved in the regulation of cell division, metabolism, gene silencing and genetic material repair as well as apoptosis. Thus far, only several well-known research teams have been studying plant proteins resembling animal sirtuins. Considering the fact how essential functions sirtuins play in other organisms, it is extremely interesting to understand their role in plants, especially that the knowledge about them is still limited. It is believed that the function of sirtuins in Arabidopsis thaliana is associated with mitochondrial energy metabolism. Possibly they may also control the synthesis of auxins or proteins involved in their transport, or they may be responsible for regulating cellular response to auxin action. In rice, sirtuins are necessary for the protection against genomic instability and cell damage that guarantee their growth. They also take part in a defensive response against Pseudomonas syringae. They may also be involved in the ripening of fruits. Moreover, their functions are associated with photosynthetic activity and aging of leaves.     

Macrophage Migration Inhibitory Factor Coordinates DNA Damage Response with the Proteasomal Control of the Cell Cycle

Proper repair of DNA damage is critical for protecting genomic stability, cellular viability and suppression of tumorigenesis. Both p53-dependent and p53-independent pathways have evolved to coordinate the cellular response following DNA damage. In this review, we highlight the importance of the ubiquitously expressed protein macrophage migration inhibitory factor (MIF) for an appropriate response to DNA damage. We discuss the mechanisms by which MIF affects the activity of the ubiquitin-proteasome system, and how this impacts on the integrity of the genome and on cancer.     

长寿蛋白SIRT6在肿瘤发生发展中的作用

SIRT6作为组蛋白去乙酰化转移酶(Histone deacetylases,HDACs)第三家族长寿蛋白(Sirtuins,SIRTs)中的一员,具有多种催化酶活性,且在抗衰老、染色质调节、转录调控、糖脂代谢、DNA损伤修复等生物学过程中起着重要的作用。近年来的证据表明,SIRT6的表达与肿瘤的发生发展密切相关,且在多种肿瘤中起着关键的调节作用,比如肝癌、肺癌、乳腺癌和生殖系统肿瘤等。但是由于SIRT6功能的多样性,及其上下游信号通路的复杂性,SIRT6在肿瘤中可能扮演着双重角色。在大多数情况下,SIRT6扮演着抑癌基因的角色,少数情况下,SIRT6却又发挥着促癌作用。本文结合目前本实验室的研究,阐述了近几年来关于SIRT6在多种肿瘤发生及发展中的最新发现,总结了其作用机制,并对其研究及应用前景进行了展望。     

Differential Impact of Tumor Suppressor Pathways on DNA Damage Response and Therapy-Induced Transformation in a Mouse Primary Cell Model

The RB and p53 tumor suppressors are mediators of DNA damage response, and compound inactivation of RB and p53 is a common occurrence in human cancers. Surprisingly, their cooperation in DNA damage signaling in relation to tumorigenesis and therapeutic response remains enigmatic. In the context of individuals with heritable retinoblastoma, there is a predilection for secondary tumor development, which has been associated with the use of radiation-therapy to treat the primary tumor. Furthermore, while germline mutations of the p53 gene are critical drivers for cancer predisposition syndromes, it is postulated that extrinsic stresses play a major role in promoting varying tumor spectrums and disease severities. In light of these studies, we examined the tumor suppressor functions of these proteins when challenged by exposure to therapeutic stress. To examine the cooperation of RB and p53 in tumorigenesis, and in response to therapy-induced DNA damage, a combination of genetic deletion and dominant negative strategies was employed. Results indicate that loss/inactivation of RB and p53 is not sufficient for cellular transformation. However, these proteins played distinct roles in response to therapy-induced DNA damage and subsequent tumorigenesis. Specifically, RB status was critical for cellular response to damage and senescence, irrespective of p53 function. Loss of RB resulted in a dramatic evolution of gene expression as a result of alterations in epigenetic programming. Critically, the observed changes in gene expression have been specifically associated with tumorigenesis, and RB-deficient, recurred cells displayed oncogenic characteristics, as well as increased resistance to subsequent challenge with discrete therapeutic agents. Taken together, these findings indicate that tumor suppressor functions of RB and p53 are particularly manifest when challenged by cellular stress. In the face of such challenge, RB is a critical suppressor of tumorigenesis beyond p53, and RB-deficiency could promote significant cellular evolution, ultimately contributing to a more aggressive disease.     

衰老或肿瘤：癌基因诱导的双向性

在大部分的肿瘤中都发现有癌基因的活化,癌基因的活化被认为是导致肿瘤发生的重要原因．然而,在野生型细胞内,癌基因的活化可以诱导细胞衰老,称为癌基因诱导的细胞衰老(oncogene-induced senescence, OIS),从而抑制进一步的肿瘤发生．因而,癌基因的活化具有诱导衰老或肿瘤的双向性．DNA损伤调控反应(DNA damage checkpoint response, DDR)是细胞应对DNA损伤时感应损伤,从而延迟或阻滞细胞周期进程的一种分子信号传递通路,是诱导细胞衰老的重要机制．癌基因的活化可以引发DNA损伤信号的产生,从而激活DDR,诱导细胞衰老．在DDR异常时,癌基因的激活可引发DNA的过度复制与细胞的过度增殖,并导致基因组不稳定性的积累,最终导致肿瘤发生．DDR的完整性决定了癌基因诱导的双向性．DDR在癌基因诱导中的重要作用,提示了保持和恢复DDR的完整性可以作为肿瘤预防和治疗的新方向．     

去乙酰化酶Sirtuin与衰老的研究进展

Sirtuin蛋白是一组具有NAD⁺依赖性的组蛋白去乙酰基转移酶,该家族成员具有高度保守的催化结构域,可以通过对多种底物进行去乙酰化作用,从而在机体内参与一系列的生物学活动,包括维持细胞抗胁迫能力和基因组稳定性以及参与能量代谢等．Sir2参与了酵母的交配型基因、端粒和rDNA 重复序列的沉默以及细胞寿命等生理功能．在哺乳动物中,SIRT1是该家族中目前研究最为广泛且较为透彻的成员,而SIRT6的功能研究成为近年来继SIRT1后的又一新热点．综述了sirtuin蛋白的结构及其与衰老关系的研究进展．     

SIRT7: a sentinel of genome stability

SIRT7 is a class III histone deacetylase that belongs to the sirtuin family. The past two decades have seen numerous breakthroughs in terms of understanding SIRT7 biological function. We now know that this enzyme is involved in diverse cellular processes, ranging from gene regulation to genome stability, ageing and tumorigenesis. Genomic instability is one hallmark of cancer and ageing; it occurs as a result of excessive DNA damage. To counteract such instability, cells have evolved a sophisticated regulated DNA damage response mechanism that restores normal gene function. SIRT7 seems to have a critical role in this response, and it is recruited to sites of DNA damage where it recruits downstream repair factors and directs chromatin regulation. In this review, we provide an overview of the role of SIRT7 in DNA repair and maintaining genome stability. We pay particular attention to the implications of SIRT7 function in cancer and ageing.     

Silencing Sirtuin 6 induces cell cycle arrest and apoptosis in non-small cell lung cancer cell lines

Sirtuins (SIRT1–7), are NAD-dependent deacetylases and ADP-ribosyl transferases, plays a major part in carcinogenesis. The previous report suggests that in cancer, sirtuins gained tremendous interest and critical regulators of the unusual processes. In carcinogenesis, sirtuins possess either tumor suppressor or promoter. However, in lung cancer condition the studies of sirtuins are less studied. Hence, this designed study investigates the impact of multifaceted sirtuins in NSCLC cells. We evaluated the mRNA and protein expressions of sirtuins by RTPCR and western blot. We found SIRT6 significantly overexpressed in NCI-H520, A549, and NCI-H460 compared with the normal BEAS-2B cell line. Silencing of SIRT6 by siRNA in NSCLC cells caused activation of p53/p21 mediated inhibition of cell proliferation leading to arrest in cell cycle and apoptosis induction. Our results implied that SIRT6 is a tumor promoter in NSCLC development, progression, and regulation. The silencing of SIRT6 to be a novel therapy for lung cancer.     

Suppression of Akt-mTOR Pathway-A Novel Component of Oncogene Induced DNA Damage Response Barrier in Breast Tumorigenesis

DNA damage has been thought to be directly associated with the neoplastic progression by enabling mutations in tumor suppressor genes and activating/and amplifying oncogenes ultimately resulting in genomic instability. DNA damage causes activation of the DNA damage response (DDR) that is an important cellular mechanism for maintaining genomic integrity in the face of genotoxic stress. While the cellular response to genotoxic stress has been extensively studied in cancer models, less is known about the cellular response to oncogenic stress in the premalignant context. In the present study, by using breast tissues samples from women at different risk levels for invasive breast cancer (normal, proliferative breast disease and ductal carcinoma in situ) we found that DNA damage is inversely correlated with risk of invasive breast cancer. Similarly, in MCF10A based in vitro model system where we recapitulated high DNA damage conditions as seen in patient samples by stably cloning in cyclin E, we found that high levels of oncogene induced DNA damage, by triggering inhibition of a major proliferative pathway (AKT), inhibits cell growth and causes cells to die through autophagy. These data suggest that AKT-mTOR pathway is a novel component of oncogene induced DNA damage response in immortalized ‘normal-like’ breast cells and its suppression may contribute to growth arrest and arrest of the breast tumorigenesis.     

Combating cellular senescence by sirtuins: Implications for atherosclerosis

Cellular senescence is the permanent cell cycle arrest induced either by chronological ageing or extrinsic stimuli. Recent researches have identified cellular senescence as an important mechanism for atherosclerosis, which is the essential pathophysiological contributor to cardiovascular diseases (CVDs). The sirtuins are a family of cellular deacetylases with fundamental abilities to regulate cellular metabolism and a variety of physiological activities. Previous studies have revealed the anti-ageing functions of sirtuins as the longevity-associated proteins. These advances indicate the potential beneficial functions of sirtuins in atherosclerosis by affecting cellular senescence. Herein, we review the recent findings about sirtuins in regulating atherosclerotic cellular senescence, and discuss the possibility of activating sirtuins as a therapeutic strategy for combating atherosclerosis.     

The emerging role of deubiquitinating enzymes in genomic integrity,diseases, and therapeutics

The addition of mono-ubiquitin or poly-ubiquitin chain to signaling proteins in response to DNA damage signal is thought to be a critical event that facilitates the recognition of DNA damage lesion site, the activation of checkpoint function, termination and checkpoint response and the recruitment of DNA repair proteins. Despite the ubiquitin modifiers, removal of ubiquitin from the functional proteins by the deubiquitinating enzymes (DUBs) plays an important role in orchestrating DNA damage response as well as DNA repair processes. Deregulated ubiquitination and deubiquitination could lead to genome instability that in turn causes tumorigenesis. Recent TCGA study has further revealed the connection between mutations in alteration of DUBs and various types of tumors. In addition, emerging drug design based on DUBs provides a new avenue for anti-cancer therapy. In this review, we will summarize the role of deubiquitination and specificity of DUBs, and highlight the recent discoveries of DUBs in the modulation of ubiquitin-mediated DNA damage response and DNA damage repair. We will furthermore discuss the DUBs involved in the tumorigenesis as well as interception of deubiquitination as a novel strategy for anti-cancer therapy.     

Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night

Autophagy is the mechanism by which cells consume parts of themselves to survive starvation and stress. This self-cannibalization limits cell death and tissue inflammation, recycles energy and biosynthetic substrates and removes damaged proteins and organelles, accumulation of which is toxic. In normal tissues, autophagy-mediated damage mitigation may suppress tumorigenesis, while in advanced tumors macromolecular recycling may support survival by buffering metabolic demand under stress. As a result, autophagy-activation in normal cells may suppress tumorigenesis, while autophagy inhibition may be beneficial for the therapy of established tumors. The mechanisms by which autophagy supports cancer cell metabolism are slowly emerging. As cancer is being increasingly recognized as a metabolic disease, how autophagy-mediated catabolism impacts cellular and mammalian metabolism and tumor growth is of great interest. Most cancer therapeutics induce autophagy, either directly by modulating signaling pathways that control autophagy in the case of many targeted therapies, or indirectly in the case of cytotoxic therapy. However, the functional consequence of autophagy induction in the context of cancer therapy is not yet clear. A better understanding of how autophagy modulates cell metabolism under various cellular stresses and the consequences of this on tumorigenesis will help develop better therapeutic strategies against cancer prevention and treatment.