Cell cycle and apoptosis regulator 2 at the interface between DNA damage response and cell physiology

Martina Magni, Giacomo Buscemi, Laura Zannini

Research output: Contribution to journalReview article

Abstract

Cell cycle and apoptosis regulator 2 (CCAR2 or DBC1) is a human protein recently emerged as a novel and important player of the DNA damage response (DDR). Indeed, upon genotoxic stress, CCAR2, phosphorylated by the apical DDR kinases ATM and ATR, increases its binding to the NAD+-dependent histone deacetylase SIRT1 and inhibits SIRT1 activity. This event promotes the acetylation and activation of p53, a SIRT1 target, and the subsequent induction of p53 dependent apoptosis. In addition, CCAR2 influences DNA repair pathway choice and promotes the chromatin relaxation necessary for the repair of heterochromatic DNA lesions. However, besides DDR, CCAR2 is involved in several other cellular functions. Indeed, through the interaction with transcription factors, nuclear receptors, epigenetic modifiers and RNA polymerase II, CCAR2 regulates transcription and transcript elongation. Moreover, promoting Rev-erbα protein stability and repressing BMAL1 and CLOCK expression, it was reported to modulate the circadian rhythm. Through SIRT1 inhibition, CCAR2 is also involved in metabolism control and, suppressing RelB and p65 activities in the NFkB pathway, it restricts B cell proliferation and immunoglobulin production. Notably, CCAR2 expression is deregulated in several tumors and, compared to the non-neoplastic counterpart, it may be up- or down-regulated. Since its up-regulation in cancer patients is usually associated with poor prognosis and its depletion reduces cancer cell growth in vitro, CCAR2 was suggested to act as a tumor promoter. However, there is also evidence that CCAR2 functions as a tumor suppressor and therefore its role in cancer formation and progression is still unclear. In this review we discuss CCAR2 functions in the DDR and its multiple biological activities in unstressed cells.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalMutation Research
Volume776
DOIs
Publication statusPublished - May 29 2018

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Cell Physiological Phenomena
DNA Damage
Cell Cycle
Apoptosis
Neoplasms
DNA Repair
rev Gene Products
Histone Deacetylases
RNA Polymerase II
Protein Stability
Acetylation
Cytoplasmic and Nuclear Receptors
Circadian Rhythm
Epigenomics
Carcinogens
NAD
Chromatin
Immunoglobulins
B-Lymphocytes
Transcription Factors

Keywords

  • Adaptor Proteins, Signal Transducing/genetics
  • Apoptosis/genetics
  • B-Lymphocytes/immunology
  • Cellular Senescence/genetics
  • Chromatin Assembly and Disassembly/genetics
  • Circadian Clocks/genetics
  • DNA Damage/genetics
  • DNA Repair/genetics
  • Epigenesis, Genetic
  • Humans
  • Models, Biological
  • Mutation
  • Neoplasms/etiology
  • Sirtuin 1/genetics
  • Transcription, Genetic
  • Tumor Suppressor Protein p53/genetics

Cite this

Cell cycle and apoptosis regulator 2 at the interface between DNA damage response and cell physiology. / Magni, Martina; Buscemi, Giacomo; Zannini, Laura.

In: Mutation Research, Vol. 776, 29.05.2018, p. 1-9.

Research output: Contribution to journalReview article

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abstract = "Cell cycle and apoptosis regulator 2 (CCAR2 or DBC1) is a human protein recently emerged as a novel and important player of the DNA damage response (DDR). Indeed, upon genotoxic stress, CCAR2, phosphorylated by the apical DDR kinases ATM and ATR, increases its binding to the NAD+-dependent histone deacetylase SIRT1 and inhibits SIRT1 activity. This event promotes the acetylation and activation of p53, a SIRT1 target, and the subsequent induction of p53 dependent apoptosis. In addition, CCAR2 influences DNA repair pathway choice and promotes the chromatin relaxation necessary for the repair of heterochromatic DNA lesions. However, besides DDR, CCAR2 is involved in several other cellular functions. Indeed, through the interaction with transcription factors, nuclear receptors, epigenetic modifiers and RNA polymerase II, CCAR2 regulates transcription and transcript elongation. Moreover, promoting Rev-erbα protein stability and repressing BMAL1 and CLOCK expression, it was reported to modulate the circadian rhythm. Through SIRT1 inhibition, CCAR2 is also involved in metabolism control and, suppressing RelB and p65 activities in the NFkB pathway, it restricts B cell proliferation and immunoglobulin production. Notably, CCAR2 expression is deregulated in several tumors and, compared to the non-neoplastic counterpart, it may be up- or down-regulated. Since its up-regulation in cancer patients is usually associated with poor prognosis and its depletion reduces cancer cell growth in vitro, CCAR2 was suggested to act as a tumor promoter. However, there is also evidence that CCAR2 functions as a tumor suppressor and therefore its role in cancer formation and progression is still unclear. In this review we discuss CCAR2 functions in the DDR and its multiple biological activities in unstressed cells.",
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author = "Martina Magni and Giacomo Buscemi and Laura Zannini",
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T1 - Cell cycle and apoptosis regulator 2 at the interface between DNA damage response and cell physiology

AU - Magni, Martina

AU - Buscemi, Giacomo

AU - Zannini, Laura

N1 - Copyright © 2018 Elsevier B.V. All rights reserved.

PY - 2018/5/29

Y1 - 2018/5/29

N2 - Cell cycle and apoptosis regulator 2 (CCAR2 or DBC1) is a human protein recently emerged as a novel and important player of the DNA damage response (DDR). Indeed, upon genotoxic stress, CCAR2, phosphorylated by the apical DDR kinases ATM and ATR, increases its binding to the NAD+-dependent histone deacetylase SIRT1 and inhibits SIRT1 activity. This event promotes the acetylation and activation of p53, a SIRT1 target, and the subsequent induction of p53 dependent apoptosis. In addition, CCAR2 influences DNA repair pathway choice and promotes the chromatin relaxation necessary for the repair of heterochromatic DNA lesions. However, besides DDR, CCAR2 is involved in several other cellular functions. Indeed, through the interaction with transcription factors, nuclear receptors, epigenetic modifiers and RNA polymerase II, CCAR2 regulates transcription and transcript elongation. Moreover, promoting Rev-erbα protein stability and repressing BMAL1 and CLOCK expression, it was reported to modulate the circadian rhythm. Through SIRT1 inhibition, CCAR2 is also involved in metabolism control and, suppressing RelB and p65 activities in the NFkB pathway, it restricts B cell proliferation and immunoglobulin production. Notably, CCAR2 expression is deregulated in several tumors and, compared to the non-neoplastic counterpart, it may be up- or down-regulated. Since its up-regulation in cancer patients is usually associated with poor prognosis and its depletion reduces cancer cell growth in vitro, CCAR2 was suggested to act as a tumor promoter. However, there is also evidence that CCAR2 functions as a tumor suppressor and therefore its role in cancer formation and progression is still unclear. In this review we discuss CCAR2 functions in the DDR and its multiple biological activities in unstressed cells.

AB - Cell cycle and apoptosis regulator 2 (CCAR2 or DBC1) is a human protein recently emerged as a novel and important player of the DNA damage response (DDR). Indeed, upon genotoxic stress, CCAR2, phosphorylated by the apical DDR kinases ATM and ATR, increases its binding to the NAD+-dependent histone deacetylase SIRT1 and inhibits SIRT1 activity. This event promotes the acetylation and activation of p53, a SIRT1 target, and the subsequent induction of p53 dependent apoptosis. In addition, CCAR2 influences DNA repair pathway choice and promotes the chromatin relaxation necessary for the repair of heterochromatic DNA lesions. However, besides DDR, CCAR2 is involved in several other cellular functions. Indeed, through the interaction with transcription factors, nuclear receptors, epigenetic modifiers and RNA polymerase II, CCAR2 regulates transcription and transcript elongation. Moreover, promoting Rev-erbα protein stability and repressing BMAL1 and CLOCK expression, it was reported to modulate the circadian rhythm. Through SIRT1 inhibition, CCAR2 is also involved in metabolism control and, suppressing RelB and p65 activities in the NFkB pathway, it restricts B cell proliferation and immunoglobulin production. Notably, CCAR2 expression is deregulated in several tumors and, compared to the non-neoplastic counterpart, it may be up- or down-regulated. Since its up-regulation in cancer patients is usually associated with poor prognosis and its depletion reduces cancer cell growth in vitro, CCAR2 was suggested to act as a tumor promoter. However, there is also evidence that CCAR2 functions as a tumor suppressor and therefore its role in cancer formation and progression is still unclear. In this review we discuss CCAR2 functions in the DDR and its multiple biological activities in unstressed cells.

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KW - Apoptosis/genetics

KW - B-Lymphocytes/immunology

KW - Cellular Senescence/genetics

KW - Chromatin Assembly and Disassembly/genetics

KW - Circadian Clocks/genetics

KW - DNA Damage/genetics

KW - DNA Repair/genetics

KW - Epigenesis, Genetic

KW - Humans

KW - Models, Biological

KW - Mutation

KW - Neoplasms/etiology

KW - Sirtuin 1/genetics

KW - Transcription, Genetic

KW - Tumor Suppressor Protein p53/genetics

U2 - 10.1016/j.mrrev.2018.03.004

DO - 10.1016/j.mrrev.2018.03.004

M3 - Review article

VL - 776

SP - 1

EP - 9

JO - Mutation Research

JF - Mutation Research

SN - 1873-135X

ER -