A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability

Hurov, Kristen E.; Cotta‐Ramusino, Cecilia; Elledge, Stephen J.

doi:10.1101/gad.1934210

Cited by 201 publications

(269 citation statements)

References 42 publications

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“…Genome instability also occurs in clk-2 mutant germlines, but strong alleles lead to a late G2-like cell cycle arrest. Subsequent studies on mammalian and yeast CLK-2 orthologs, referred to as TEL2 in yeasts, established that CLK-2/TEL2 is required for the full activation of all PIKKs-type protein kinases, a class of protein kinases that includes ATM/ atm-1 and ATL-1, thus explaining checkpoint-signalling phenotypes (Hayashi et al 2007 ;Kanoh and Yanagida 2007 ;Hurov et al 2010 ;Takai et al 2010 ;Kaizuka et al 2010 ) . The current model suggests that CLK-2/TEL2 might have a chaperonlike function required for the full activation of those kinases (Horejsi et al 2010 ) .…”

Section: Upstream Dna Damage Checkpoint Signalling In the C Elegans mentioning

confidence: 99%

Germ Cell Apoptosis and DNA Damage Responses

Bailly

Gartner

2012

Advances in Experimental Medicine and Biology

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In the past 12 years, since the fi rst description of C. elegans germ cell apoptosis, this area of research rapidly expanded. It became evident that multiple genetic pathways lead to the apoptotic demise of germ cells. We are only beginning to understand how these pathways that all require the CED-9/Bcl-2, Apaf-1/CED-4 and CED-3 caspase core apoptosis components are regulated. Physiological apoptosis, which likely accounts for the elimination of more than 50% of all germ cells, even in unperturbed conditions, is likely to be required to maintain tissue homeostasis. The best-studied pathways lead to DNA damage-induced germ cell apoptosis in response to a variety of genotoxic stimuli. This apoptosis appears to be regulated similar to DNA damage-induced apoptosis in the mouse germ line and converges on p53 family transcription factors. DNA damage response pathways not only lead to apoptosis induction, but also directly affect DNA repair, and a transient cell cycle arrest of mitotic germ cells. Finally, distinct pathways activate germ cell apoptosis in response to defects in meiotic recombination and meiotic chromosome pairing.

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Section: Upstream Dna Damage Checkpoint Signalling In the C Elegans mentioning

confidence: 99%

Germ Cell Apoptosis and DNA Damage Responses

Bailly

Gartner

2012

Advances in Experimental Medicine and Biology

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“…The evidence suggesting a role for FUS in DNA repair is particularly intriguing for ALS pathogenesis, given growing evidence that RNA binding proteins are active in the prevention and repair of transcription-associated DNA damage (8)(9)(10)(11)(12). Other ALS-related RNAbinding proteins like SETX, EWSR1, and TAF15 have also been linked to DNA damage and repair, further suggesting the importance of a breakdown in this process in ALS pathogenesis (11,(13)(14)(15)(16).…”

Section: Dna Damage Response | Als | Transcription | R Loopmentioning

confidence: 99%

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Hill

Mordes

Cameron

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

108

119

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loopassociated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.A myotrophic lateral sclerosis (ALS) is a disease of both upper and lower motor neuron dysfunction that leads to progressive paralysis and eventually death due to respiratory failure. No single model of ALS disease pathogenesis has been revealed; however, multiple disease-associated genes are known (1). The variation in function of these genes suggests that there may be multiple ALS molecular subtypes. That said, the familial ALS gene product list is also enriched in protein groups with related functions.Mutations in multiple RNA processing genes, including FUS (FUS RNA-binding protein), TDP43 (TAR DNA-binding protein), SETX (senataxin), TAF15 (TATA box-binding protein-associated factor 15), EWSR1 (EWS RNA-binding protein 1), HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), and HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), among others, give rise to familial ALS (fALS) (1). FUS and TDP43 are currently the best studied, given that mutations in these genes lead to classic histologic findings in ALS neural tissue and that similar histologic findings can be found in neural tissue of sporadic ALS cases (2). At autopsy, cytoplasmic TDP43 inclusions are found in ALS motor neurons from patients with (i) TDP43 mutations and (ii) sporadic ALS (i.e., patients with no FUS, TDP43, or other known pathogenic mutation) (2). They are also present in neurons in various parts of the brains of patients with either sporadic or familial versions of the ALS-related disorder, fronto-temporal lobar dementia (FTLD) (2). At autopsy, FUS inclusions were detected in the cytoplasm of motor neurons of FUS mutation-bearing fALS patients and in the cytoplasm of neurons in various regions of the brain in some FTLD patients (2).FUS and TDP43 exhibit a wide range of functions, most of which involv...

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“…57 Recent studies have also reported that TEL2 forms a 2-MDa complex with TTI1, TTI2, and Hsp90 chaperones, which is required for PIKK stability. 58,59 These studies indicate that TEL2 interacts with newly synthesized PIKKs and does not associate efficiently with the activated, mature form of ATM. Another group also reported that the (AAA+) family proteins RuvB-like 1 (RUVBL1) and RUVBL2 control PIKK abundance at least at the mRNA level, and also form a complex with Hsp90.…”

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confidence: 97%