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The telomeric repeat‐containing RNA, TERRA, associates with both telomeric DNA and telomeric proteins, often forming RNA:DNA hybrids (R‐loops). TERRA is most abundant in cancer cells utilizing the alternative lengthening of telomeres (ALT) pathway for telomere maintenance, suggesting that persistent TERRA R‐loops may contribute to activation of the ALT mechanism. Therefore, we sought to identify the enzyme(s) that regulate TERRA metabolism in mammalian cells. Here, we identify that the 5′–3′ exoribonuclease XRN2 regulates the stability of TERRA RNA. Moreover, while stabilization of TERRA alone was insufficient to drive ALT, depletion of XRN2 in ALT‐positive cells led to a significant increase in TERRA R‐loops and exacerbated ALT activity. Together, our findings highlight XRN2 as a key determinant of TERRA metabolism and telomere stability in cancer cells that rely on the ALT pathway. [ABSTRACT FROM AUTHOR]

α‐Tthalassemia mental retardation X‐linked (ATRX) is a chromatin remodeler frequently mutated in many cancers. Despite the binding pattern of ATRX in heterochromatin, ATRX‐mediated epigenomic changes in cancer cells have not been profiled, especially for the heterochromatin regions. Here, we profiled genome‐wide maps of chromatin accessibility in ATRX‐intact and ATRX‐null human cancer cells. We found extensive changes in chromatin accessibility in both repetitive DNA regions and non‐repetitive regulatory regions following ATRX loss. These changes are highly correlated with changes in transcription, which lead to alterations in cancer‐related signalling pathways, such as upregulation of the TGF‐β pathway and downregulation of the cadherin family of proteins. These findings indicate that ATRX deficiency induces epigenomic changes and promotes tumorigenesis through both genome instability and shifts in transcription. [ABSTRACT FROM AUTHOR]

Cellular differentiation, developmental processes, and environmental factors challenge the integrity of the proteome in every eukaryotic cell. The maintenance of protein homeostasis, or proteostasis, involves folding and degradation of damaged proteins, and is essential for cellular function, organismal growth, and viability . Misfolded proteins that cannot be refolded by chaperone machineries are degraded by specialized proteolytic systems. A major degradation pathway regulating cellular proteostasis is the ubiquitin (Ub)/proteasome system ( UPS), which regulates turnover of damaged proteins that accumulate upon stress and during aging. Despite a large number of structurally unrelated substrates, Ub conjugation is remarkably selective. Substrate selectivity is mainly provided by the group of E3 enzymes. Several observations indicate that numerous E3 Ub ligases intimately collaborate with molecular chaperones to maintain the cellular proteome. In this review, we provide an overview of specialized quality control E3 ligases playing a critical role in the degradation of damaged proteins. The process of substrate recognition and turnover, the type of chaperones they team up with, and the potential pathogeneses associated with their malfunction will be further discussed. [ABSTRACT FROM AUTHOR]