Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging

Brosh, Robert M.; Bellani, Marina A.; Liu, Yie; Seidman, Michael M.

doi:10.1016/j.arr.2016.05.005

Cited by 57 publications

(62 citation statements)

References 113 publications

(125 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, several lines of evidence imply continued exposure of SCs to DNA damage plays a major role in age-related dysfunctions such as cancer and degenerative diseases [1,3,9,16,[57][58][59][60][61][62]. Eventually, unrepaired genetic lesions may result in SC attrition, cellular transformation and aberrant differentiation that could lead to defective tissue renewal [1,3,9,10,[61][62][63]. It is unclear whether the increased genome alterations are due to individual or combined effects of: (i) impaired DDR, (ii) increased levels of DNA insults, (iii) epigenetic modifications and telomere shortening with age, (iv) higher susceptibility to damaging agents in SC and progenitor populations (e.g.…”

Section: Tissue Renewal and Stem Cell Response To Dna Damagementioning

confidence: 99%

DNA damage and tissue repair: What we can learn from planaria

Barghouth

Thiruvalluvan

LeGro

et al. 2019

Seminars in Cell & Developmental Biology

View full text Add to dashboard Cite

Faithful renewal of aging and damaged tissues is central to organismal lifespan. Stem cells (SCs) generate the cellular progeny that replenish adult tissues across the body but this task becomes increasingly compromised over time. The age related decline in SC-mediated tissue maintenance is a multifactorial event that commonly affects genome integrity. The presence of DNA damage in SCs that are under continuous demand to divide poses a great risk for age-related disorders such as cancer. However, performing analysis of SCs with genomic instability and the DNA damage response during tissue renewal present significant challenges. Here we introduce an alternative experimental system based on the planaria flatworm Schmidtea mediterranea to address at the organismal level studies intersecting SC-mediated tissue renewal in the presence of genomic instability. Planaria have abundant SCs (neoblasts) that maintain high rates of cellular turnover and a variety of molecular tools have been developed to induce DNA damage and dissect how neoblasts respond to this stressor. S. mediterranea displays high evolutionary conservation of DNA repair mechanisms and signaling pathways regulating adult SCs. We describe genetically induced-DNA damage models and highlight body-wide signals affecting cellular decisions such as survival, proliferation, and death in the presence of genomic instability. We also discuss transcriptomic changes in the DNA damage response during injury repair and propose DNA repair as key component of tissue regeneration. Additional studies using planaria will provide insights about mechanisms regulating survival and growth of cells with DNA damage during tissue renewal and regeneration.

show abstract

Section: Tissue Renewal and Stem Cell Response To Dna Damagementioning

confidence: 99%

DNA damage and tissue repair: What we can learn from planaria

Barghouth

Thiruvalluvan

LeGro

et al. 2019

Seminars in Cell & Developmental Biology

View full text Add to dashboard Cite

show abstract

“…However, cells from FA individuals are hypersensitive to agents that induce oxidative stress [134] and display elevated oxidatively damaged DNA [135], including 8-oxoG [136], consistent with elevated ROS and mitochondrial dysfunction [137, 138]. The elevated ROS in FA is thought to arise from increased circulatory inflammatory cytokines [139, 140], which in turn may be stimulated by oxidatively damaged DNA (reviewed in [141]) (Fig. 3).…”

Section: Fanconi Anemia Pathway Oxidative Stress Fancj Helicase Anmentioning

confidence: 99%

Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism

Crouch

Brosh

2017

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

Cells are under constant assault from reactive oxygen species that occur endogenously or arise from environmental agents. An important consequence of such stress is the generation of oxidatively damaged DNA, which is represented by a wide range of non-helix distorting and helix-distorting bulkier lesions that potentially affect a number of pathways including replication and transcription; consequently DNA damage tolerance and repair pathways are elicited to help cells cope with the lesions. The cellular consequences and metabolism of oxidatively damaged DNA can be quite complex with a number of DNA metabolic proteins and pathways involved. Many of the responses to oxidative stress involve a specialized class of enzymes known as helicases, the topic of this review. Helicases are molecular motors that convert the energy of nucleoside triphosphate hydrolysis to unwinding of structured polynucleic acids. Helicases by their very nature play fundamentally important roles in DNA metabolism and are implicated in processes that suppress chromosomal instability, genetic disease, cancer, and aging. We will discuss the roles of helicases in response to nuclear and mitochondrial oxidative stress and how this important class of enzymes help cells cope with oxidatively generated DNA damage through their functions in the replication stress response, DNA repair, and transcriptional regulation.

show abstract

“…Endogenously produced ICLs are believed to represent a major threat to genome integrity, illustrated by a rare inherited syndrome Fanconi anaemia (FA), associated with defective ICL repair (Duxin & Walter, 2015). FA patients suffer from bone marrow failure, predisposition to solid tumours and numerous developmental defects (Brosh et al, 2017). ICL toxicity is also exploited in cancer chemotherapy, where the antiproliferative effects of a number of clinically important drugs (platinum agents, nitrogen mustards and mitomycin C) result from ICL induction (McHugh et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

RPA activates the XPF ‐ ERCC 1 endonuclease to initiate processing of DNA interstrand crosslinks

et al. 2017

View full text Add to dashboard Cite

During replication‐coupled DNA interstrand crosslink (ICL) repair, the XPF‐ERCC1 endonuclease is required for the incisions that release, or “unhook”, ICLs, but the mechanism of ICL unhooking remains largely unknown. Incisions are triggered when the nascent leading strand of a replication fork strikes the ICL. Here, we report that while purified XPF‐ERCC1 incises simple ICL‐containing model replication fork structures, the presence of a nascent leading strand, modelling the effects of replication arrest, inhibits this activity. Strikingly, the addition of the single‐stranded DNA (ssDNA)‐binding replication protein A (RPA) selectively restores XPF‐ERCC1 endonuclease activity on this structure. The 5′–3′ exonuclease SNM1A can load from the XPF‐ERCC1‐RPA‐induced incisions and digest past the crosslink to quantitatively complete the unhooking reaction. We postulate that these collaborative activities of XPF‐ERCC1, RPA and SNM1A might explain how ICL unhooking is achieved in vivo.

show abstract

Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging

Cited by 57 publications

References 113 publications

DNA damage and tissue repair: What we can learn from planaria

DNA damage and tissue repair: What we can learn from planaria

Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism

RPA activates the XPF ‐ ERCC 1 endonuclease to initiate processing of DNA interstrand crosslinks

Contact Info

Product

Resources

About