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DNA Damage Response Pathways in Cancer Predisposition and Progression

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Genomic Instability and Cancer Metastasis

Part of the book series: Cancer Metastasis - Biology and Treatment ((CMBT,volume 20))

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Abstract

Cells are continually challenged by DNA assaults from endogenous and exogenous sources. Without appropriate repair, DNA damage can cause genome instability and the development of various diseases such as cancer, Immunodeficiency, neurological abnormalities, and premature aging. To maintain genome integrity, cells have evolved highly conserved defense mechanisms, collectively known as the DNA damage response (DDR), to identify the lesions, signal their presence, and activate the appropriate DNA repair pathway. In this chapter, we will discuss the recent advances in DDR, cancers with heritable defect in DNA repair, and secondary cancers developed following treatment with chemotherapeutic drugs that damage the DNA. We will focus on four major repair pathways with particular attention to the exploitation of recent knowledge to improve cancer therapy.

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Abbreviations

5′ dRP:

5′ deoxyribose phosphate

8-oxodG:

7,8 dihydro-8-oxo-2′-deoxyguanosine

8-oxoGua:

8-oxo-7,8-dihydroguanine

9-1-1:

Rad9-Rad1-Hus1

AML:

Acute myeloid leukemia

A-NHEJ:

Alternative NHEJAPE-1:Apurinic endonuclease

aCGH:

Array comparative genomic hybridization

B-CLL:

B-cell chronic lymphocytic leukemia

BER:

Base excision repair

BIR:

Break-induced replication

BMF:

Bone marrow failure

C-NHEJ:

Classical NHEJ

CRC:

Colorectal cancer

DDR:

DNA damage response

dHJ:

Double Holliday junction

DSB:

Double strand break

DSBR:

DSB repair

dsDNA:

Double-stranded DNA

EC:

Endometrial cancer

EDM:

Exonuclease domain mutations

FA:

Fanconi anemia

hESC:

Human embryonic stem cell

HSC:

Hematopoietic stem cell

HR:

Homologous recombination

ICLs:

Interstrand crosslinks

IDLs:

Insertion-deletion loops

iPSC:

Induced pluripotent stem cells

IR:

Ionizing radiation

LS:

Lynch syndrome

MGMT:

Methylguanine methyltransferase

MIN or MSI:

Microsatellite instability

MMR:

Mismatch repair

NEIL1:

Endonuclease VIII-like 1

NHEJ:

Non-Homologous end joining

OGG1:

8-oxoguanine glycosylase

PAR:

Poly ADP-ribose

PARG:

Poly(ADP-ribose) glycohydrolase

PARP:

poly (ADP-ribose) polymerase

PNK:

polynucleotide kinase

PUA:

α, ß-unsaturated aldehyde

ROS:

Reactive oxygen species

SCE:

Sister chromatid exchange

SL:

Synthetic lethality

SSA:

Single-strand annealing

SSB:

Single strand break

SSBR:

SSB repair

SSDA:

Synthesis-dependent strand annealingss DNA Single-stranded DNA

t-AML:

Therapy-related AML

TLS:

Translesion synthesis

t-MDS:

Therapy-related myelodysplastic syndrome

t-MDS/MPN:

Therapy-related myelodysplastic/myeloproliferative neoplasms

UAF1:

USP1-associated protein

USP1:

Ubiquitin-specific peptidase 1

t-MN:

Therapy-related myeloid neoplasms

UV:

Ultraviolet

VUS:

Variants of uncertain significance

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Authors and Affiliations

  1. Center for Genomics, Helmy Institute, Zewail City of Science and Technology, Giza, Egypt

    Mohamed E. Ashour, Lamia El-Shafie & Sherif F. El-Khamisy

  2. Krebs Institute, University of Sheffield, Sheffield, UK

    Sherif F. El-Khamisy

Authors
  1. Mohamed E. Ashour
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  2. Lamia El-Shafie
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  3. Sherif F. El-Khamisy
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Correspondence to Sherif F. El-Khamisy .

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Editors and Affiliations

  1. Child & Family Research Institute, University of British Columbia, Pediatrics, Vancouver, British Columbia, Canada

    Chris Maxwell

  2. Dept of Cellular & Physiological Sciences, University of British Columbia, Dept. of Cellular & Physiological Sciences, Vancouver, British Columbia, Canada

    Cal Roskelley

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Ashour, M., El-Shafie, L., El-Khamisy, S. (2015). DNA Damage Response Pathways in Cancer Predisposition and Progression. In: Maxwell, C., Roskelley, C. (eds) Genomic Instability and Cancer Metastasis. Cancer Metastasis - Biology and Treatment, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-319-12136-9_3

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