Degradation‐linked ubiquitin signal and proteasome are integral components of DNA double strand break repair: New perspectives for anti‐cancer therapy

Ramadan, Kristijan; Meerang, Mayura

doi:10.1016/j.febslet.2011.04.046

Cited by 36 publications

(36 citation statements)

References 86 publications

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“…Protein ubiquitination is a general process preceding and controlling protein degradation by UPS [27]. Therefore, we analyzed TRF2 ubiquitination in VSMC in response to doxorubicin and the effect of uPAR downregulation on this process.…”

Section: Resultsmentioning

confidence: 99%

Urokinase Receptor Mediates Doxorubicin-Induced Vascular Smooth Muscle Cell Senescence via Proteasomal Degradation of TRF2

et al. 2012

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The anthracycline doxorubicin is a widely used effective anti-cancer drug. However, its application and dosage are severely limited due to its cardiotoxicity. The exact mechanisms of doxorubicin-induced cardiotoxic side effects remain poorly understood. Even less is known about the impact of doxorubicin treatment on vascular damage. We found that low doses of doxorubicin induced a senescent response in human primary vascular smooth muscle cells (VSMC). We observed that expression of urokinase receptor (uPAR) was upregulated in response to doxorubicin. Furthermore, the level of uPAR expression played a decisive role in developing doxorubicin-induced senescence. uPAR silencing in human VSMC by means of RNA interference as well as uPAR knockout in mouse VSMC resulted in abrogation of doxorubicin-induced cellular senescence. On the contrary, uPAR overexpression promoted VSMC senescence. We further found that proteasomal degradation of telomeric repeat binding factor 2 (TRF2) mediates doxorubicin-induced VSMC senescence. Our results demonstrate that uPAR controls the ubiquitin-proteasome system in VSMC and regulates doxorubicin-induced TRF2 ubiquitination and proteasomal degradation via this mechanism. Therefore, VSMC senescence induced by low doses of doxorubicin may contribute to vascular damage upon doxorubicin treatment. uPAR-mediated TRF2 ubiquitination and proteasomal degradation are further identified as a molecular mechanism underlying this process.

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Section: Resultsmentioning

confidence: 99%

Urokinase Receptor Mediates Doxorubicin-Induced Vascular Smooth Muscle Cell Senescence via Proteasomal Degradation of TRF2

et al. 2012

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“…44 Many proteins involved in the DDR are marked with Lys48 polyubiquitin and degraded soon after the formation of a DSB. 27 However, the function of Lys48-linked ubiquitination in DSB repair was unappreciated until recently. Our work elucidated the crucial function of Lys48-ubiquitin chains in mammalian cells in vivo (Fig.…”

Section: The Ubiquitin-dependent Protein Remodeling Chaperone P97/vcpmentioning

confidence: 99%

“…For example, BRCA-1 is ubiquitinated and degraded after ionizing radiation (IR) but also exhibits E3 ubiquitin ligase activity. 27 Therefore, BRCA-1 could function as a p97 substrate, a p97 substrate processing factor or both. The ubiquitin-related functions of p97 also include the trafficking of ubiquitinated proteins to the aggresome; as such, p97 plays an important role in "cleaning" protein aggregates from cells by autophagy.…”

Section: The Ubiquitin-dependent Protein Remodeling Chaperone P97/vcpmentioning

confidence: 99%

p97/VCP- and Lys48-linked polyubiquitination form a new signaling pathway in DNA damage response

Ramadan

2012

Cell Cycle

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R NF8/RNF168-dependentLys63-linked polyubiquitination at sites of DNA double-strand breaks (DSBs) was originally regarded as the sole ubiquitin-signaling pathway involved in the DNA damage response (DDR). However, ubiquitin-dependent p97/VCP segregase activity and RNF8-dependent Lys48-linked polyubiquitin chains at DSB sites have recently been identified as components of an additional and parallel ubiquitin-signaling DDR pathway. This newly identified pathway is essential to spatiotemporal protein turnover and regulates both main branches of DSB repair, homologous recombination and nonhomologous end joining. In this report, the function of the RNF8/Lys48 polyubiquitin chains/p97 pathway is discussed in the context of DSB repair and p97 chromatin-related functions.

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“…-independent manners [68]. The accumulation of several ubiquitin ligases (E3s) such as RAD18, BRCA1, RNF8, RNF168, and HERC2 at the double-strand break (DSB) sites [69][70][71][72][73][74][75] is consistent with the role of multiple ubiquitination processes in the repair of single type of DNA damage.…”

Section: Ubiquitination and Dna Repairmentioning

confidence: 63%

Regulation of nucleotide excision repair through ubiquitination

Li¹,

Bhat²,

Xiao³

2011

ABBS

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Nucleotide excision repair (NER) is the most versatile DNA-repair pathway in all organisms. While bacteria require only three proteins to complete the incision step of NER, eukaryotes employ about 30 proteins to complete the same step. Here we summarize recent studies demonstrating that ubiquitination, a post-translational modification, plays critical roles in regulating the NER activity either dependent on or independent of ubiquitin-proteolysis. Several NER components have been shown as targets of ubiquitination while others are actively involved in the ubiquitination process. We argue through this analysis that ubiquitination serves to coordinate various steps of NER and meanwhile connect NER with other related pathways to achieve the efficient global DNA-damage response.

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Degradation‐linked ubiquitin signal and proteasome are integral components of DNA double strand break repair: New perspectives for anti‐cancer therapy

Cited by 36 publications

References 86 publications

Urokinase Receptor Mediates Doxorubicin-Induced Vascular Smooth Muscle Cell Senescence via Proteasomal Degradation of TRF2

Urokinase Receptor Mediates Doxorubicin-Induced Vascular Smooth Muscle Cell Senescence via Proteasomal Degradation of TRF2

p97/VCP- and Lys48-linked polyubiquitination form a new signaling pathway in DNA damage response

Regulation of nucleotide excision repair through ubiquitination

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