Heterochromatin-Encoded Satellite RNAs Induce Breast Cancer

Abstract

Heterochromatic repetitive satellite RNAs are extensively transcribed in a variety of human cancers, including BRCA1 mutant breast cancer. Aberrant expression of satellite RNAs in cultured cells induces the DNA damage response, activates cell cycle checkpoints, and causes defects in chromosome segregation. However, the mechanism by which satellite RNA expression leads to genomic instability is not well understood. Here we provide evidence that increased levels of satellite RNAs in mammary glands induce tumor formation in mice. Using mass spectrometry, we further show that genomic instability induced by satellite RNAs occurs through interactions with BRCA1-associated protein networks required for the stabilization of DNA replication forks. Additionally, de-stabilized replication forks likely promote the formation of RNA-DNA hybrids in cells expressing satellite RNAs. These studies lay the foundation for developing novel therapeutic strategies that block the effects of non-coding satellite RNAs in cancer cells.

BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling

“…Inherited mutations or reduced BRCA1 activity are known to increase the risk of human breast and ovarian cancers. Previously, we demonstrated aberrant expression of satellite RNAs in BRCA1-deficient tumors, which itself alone can lead to tumorigenesis by promoting genomic instability (13,14). In agreement with mutational theory, genomic instability can foster tumorigenesis by selecting cells with growth advantage, oncogene activation, or tumor suppressor inactivation.…”

“…These diverse roles are specified by interaction of BRCA1 with its heterodimeric partner BARD1 that greatly enhances the E3 ubiquitin ligase activity of the complex (12). How loss of BRCA1 activity in heterozygous carriers leads to tumorigenesis remains only partially understood (13)(14)(15).…”

Exosomes transmit retroelement RNAs to drive inflammation and immunosuppression in Ewing Sarcoma

“…Among 297 upregulated mRNAs, there were IRF7, IL8, IL32, TNFRSF14 and MB21D1/CGAS ( Fig.5e and Extended Data Table 6b), consistent with the observed activation of antiviral and proinflammatory responses. However, the largest group of upregulated mRNAs (54 of 297) were those encoding centromeric proteins and kinetochore complex assembly components ("CENPA/NDC80" module), key regulators of centrosome maturation, spindle assembly and chromatin condensation ("PLK1/NEK2" module), and other cell division and DNA damage control proteins ("BRCA1/TOP2A" module; Fig.5f and Extended Data Table 6c), all of which are known to be involved in pericentromeric heterochromatin maintenance 29,44,45 . Activation of these pathways may thus be indicative of extensive centromeric heterochromatin remodelling in recipient cells.…”

The String Decomposition Problem and its Applications to Centromere Assembly

“…Recent advancements in long read sequencing technologies, such as Pacific Biosciences (PB) and Oxford Nanopore Technologies (ONT), led to a substantial increase in the contiguity of genome assemblies (Koren et al, 2017;Kolmogorov et al, 2019;Ruan and Li, 2019;Shafin et al, 2019) and opened a possibility to resolve extra-long tandem repeats ( ETRs ), the problem that was viewed as intractable until recently. Assembling ETRs is important since variations in ETR have been linked to cancer and infertility (Barra and Fachinetti, 2018;Black and Giunta, 2018;Ferreira et al, 2015;Giunta and Funabiki, 2017;Miga et al, 2019;Smurova and De Wulf, 2018;Zhu et al, 2018) . ETR sequencing is also important for addressing open problems about centromere evolution (Alkan et al, 2007;Lower et al, 2018;Shepelev et al, 2009, Henikoff et al, 2015 .…”