Shaping DNA damage responses: Therapeutic potential of targeting telomeric proteins and DNA repair factors in cancer.

Shelterin proteins regulate genomic stability by preventing inappropriate DNA damage responses (DDRs) at telomeres. Unprotected telomeres lead to persistent DDR causing cell cycle inhibition, growth arrest, and apoptosis. Cancer cells rely on DDR to protect themselves from DNA lesions and exogenous DNA-damaging agents such as chemotherapy and radiotherapy.

Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.

Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier.

Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer.

Transcriptional reactivation of hTERT is the limiting step in tumorigenesis. While mutations in hTERT promoter present in 19% of cancers are recognized as key drivers of hTERT reactivation, mechanisms by which wildtype hTERT (WT-hTERT) promoter is reactivated, in majority of human cancers, remain unknown. Using primary colorectal cancers (CRC) we identified Tert INTeracting region 2 (T-INT2), the critical chromatin region essential for reactivating WT-hTERT promoter in CRCs.

Genome-wide screens identify specific drivers of mutant promoters.

Cancer-specific promoter mutations reported in 19% of cancers result in enhanced telomerase activity. Understanding the distinctions between transcriptional regulation of wild-type (WT) and mutant (Mut) promoters may open up avenues for development of inhibitors which specially block expression in cancer cells. To comprehensively identify physiological regulators of WT- or Mut- promoters, we generated several isogenic reporter cells driven by endogenous loci.

Chromatin interaction neural network (ChINN): a machine learning-based method for predicting chromatin interactions from DNA sequences.

Chromatin interactions play important roles in regulating gene expression. However, the availability of genome-wide chromatin interaction data is limited. We develop a computational method, chromatin interaction neural network (ChINN), to predict chromatin interactions between open chromatin regions using only DNA sequences.

Non-canonical roles of canonical telomere binding proteins in cancers.

Reactivation of telomerase is a major hallmark observed in 90% of all cancers. Yet paradoxically, enhanced telomerase activity does not correlate with telomere length and cancers often possess short telomeres; suggestive of supplementary non-canonical roles that telomerase might play in the development of cancer. Moreover, studies have shown that aberrant expression of shelterin proteins coupled with their release from shortening telomeres can further promote cancer by mechanisms independent of their telomeric role.

: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis.

Objective: NFκB is the key modulator in inflammatory disorders. However, the key regulators that activate, fine-tune or shut off NFκB activity in inflammatory conditions are poorly understood. In this study, we aim to investigate the roles that NFκB-specific long non-coding RNAs (lncRNAs) play in regulating inflammatory networks.

Long-Range Chromatin Interactions Drive Mutant TERT Promoter Activation.

Unlabelled: Cancer-specific TERT promoter mutations (-146C>T and -124C>T) have been linked to reactivation of the epigenetically silenced telomerase reverse transcriptase gene (TERT). Understanding how these single-nucleotide alterations drive TERT reactivation is a fundamental unanswered question and is key for making successful therapeutics. We show that unlike wild-type promoters, recruitment of the transcription factor GABPA specifically to mutant TERT promoters mediates long-range chromatin interaction and enrichment of active histone marks, and hence drives TERT transcription.

Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression.

Transcriptional reactivation of telomerase reverse transcriptase (TERT) reconstitutes telomerase activity in the majority of human cancers. Here, we found that ectopic TERT expression increases cell proliferation, while acute reductions in TERT levels lead to a dramatic loss of proliferation without any change in telomere length, suggesting that the effects of TERT could be telomere independent. We observed that TERT determines the growth rate of cancer cells by directly regulating global protein synthesis independently of its catalytic activity.

Reactivation of telomerase in cancer.

Activation of telomerase is a critical step in the development of about 85 % of human cancers. Levels of Tert, which encodes the reverse transcriptase subunit of telomerase, are limiting in normal somatic cells. Tert is subjected to transcriptional, post-transcriptional and epigenetic regulation, but the precise mechanism of how telomerase is re-activated in cancer cells is poorly understood.

Quantitative assessment of telomerase components in cancer cell lines.

Besides its canonical function of catalyzing the formation of telomeric repeats, many groups have recently reported non-canonical functions of hTERT in particular, and telomerase in general. Regulating transcription is the central basis of non-canonical functions of telomerase. However, unlike reverse transcriptase activity of telomerase that requires only a few molecules of enzymatically active hTERT, non-canonical functions of hTERT or other telomerase components theoretically require several hundred copies.

An oncogenic role of Agrin in regulating focal adhesion integrity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. The identity and role of cell surface molecules driving complex biological events leading to HCC progression are poorly understood, hence representing major lacunae in HCC therapies. Here, combining SILAC quantitative proteomics and biochemical approaches, we uncover a critical oncogenic role of Agrin, which is overexpressed and secreted in HCC.

NUCKS is a positive transcriptional regulator of insulin signaling.

Although much is known about the molecular players in insulin signaling, there is scant information about transcriptional regulation of its key components. We now find that NUCKS is a transcriptional regulator of the insulin signaling components, including the insulin receptor (IR). Knockdown of NUCKS leads to impaired insulin signaling in endocrine cells.

Chronic adipose tissue inflammation: all immune cells on the stage.

Inflammation is indispensable for host homeostasis against invading pathogens and efficient wound healing upon tissue malfunction and has to be tightly controlled by various mechanisms to limit excess responses harmful to host tissues. A myriad of disease conditions ranging from type 2 diabetes (T2D) to neurodegenerative and cardiovascular disorders are now shown to progress due to persistent, unresolved inflammation in metabolic tissues such as adipose, liver, pancreas, muscle, and brain. However, their underlying mechanisms are incompletely understood.

Aggregatibacter actinomycetemcomitans GroEL protein promotes conversion of human CD4+ T cells into IFNγ IL10 producing Tbet+ Th1 cells.

One of the heat shock family protein (Hsp) expressing bacteria is the gram negative, periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa). A. actinomycetemcomitans' Hsp is a 64-kDa GroEL-protein, which has been shown to influence the host cells.