DNA replication stress

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Replication stress and its consequences in mitosis Replication stress and its consequences in mitosis.png
Replication stress and its consequences in mitosis

DNA replication stress refers to the state of a cell whose genome is exposed to various stresses. The events that contribute to replication stress occur during DNA replication, and can result in a stalled replication fork. [1]

Contents

There are many events that contribute to replication stress, including: [2]

ATM and ATR are proteins that help to alleviate replication stress. [3] Specifically, they are kinases that are recruited and activated by DNA damage. [1] [2] The stalled replication fork can collapse if these regulatory proteins fail to stabilize it. [4] When this occurs, reassembly of the fork is initiated in order to repair the damaged DNA end. [4]

Replication fork

INO80 stabilizes replication forks and counteracts mislocalization of H2A.Z INO80 stabilizes replication forks and counteracts mislocalization of H2A.Z.png
INO80 stabilizes replication forks and counteracts mislocalization of H2A.Z

The replication fork consists of a group of proteins that influence the activity of DNA replication. In order for the replication fork to stall, the cell must possess a certain number of stalled forks and arrest length. The replication fork is specifically paused due to the stalling of helicase and polymerase activity, which are linked together. In this situation, the fork protection complex (FPC) is recruited to help maintain this linkage. [5]

In addition to stalling and maintaining the fork structure, protein phosphorylation can also create a signal cascade for replication restart. The protein Mrc1, which is part of the FPC, transmits the checkpoint signal by interacting with kinases throughout the cascade. When there is a loss of these kinases (from replication stress), an excess of ssDNA is produced, which is necessary for the restarting of replication. [6]

Replication block removal

DNA interstrand cross-links (ICLs) cause replication stress by blocking replication fork progression. This blockage leads to failure of DNA strand separation and a stalled replication fork. Repair of ICLs can be accomplished by sequential incisions, and homologous recombination. In vertebrate cells, replication of an ICL-containing chromatin template triggers recruitment of more than 90 DNA repair and genome maintenance factors. [7] Analysis of the proteins recruited to stalled replication forks revealed a specific set of DNA repair factors involved in the replication stress response. [7] Among these proteins, SLF1 and SLF2 were found to physically link the SMC5/6 DNA repair protein complex to RAD18. The SMC5/6 complex is employed in homologous recombination, and its linkage to RAD18 likely allows recruitment of SMC5/6 to ubiquitination products at sites of DNA damage.

Replication-coupled repair

Mechanisms that process damaged DNA in coordination with the replisome in order to maintain replication fork progression are considered to be examples of replication-coupled repair. In addition to the repair of DNA interstrand crosslinks, indicated above, multiple DNA repair processes operating in overlapping layers can be recruited to faulty sites depending on the nature and location of the damage. These repair processes include (1) removal of misincorporated bases; (2) removal of misincorporated ribonucleotides; (3) removal of damaged bases (e.g. oxidized or methylated bases) that block the replication polymerase; (4) removal of DNA-protein crosslinks; and (5) removal of double-strand breaks. [8] Such repair pathways can function to protect stalled replication forks from degradation and allow restart of broken forks, but when deficient can cause replication stress.

Single-strand break repair

Singe-strand breaks are one of the most common forms of endogenous DNA damage. [9] Replication fork collapse at leading strand nicks generates resected single-ended double-strand breaks that can be repaired by homologous recombination. [9]

Causation

Replication stress is induced from various endogenous and exogenous stresses, which are regularly introduced to the genome. [10] These stresses include, but are not limited to, DNA damage, excessive compacting of chromatin (preventing replisome access), over-expression of oncogenes, [11] or difficult-to-replicate genome structures. [1] [2] Replication stress can lead to genome instability, cancer, and ageing. [12] [13] Uncoordinated replication–transcription conflicts and unscheduled R-loop accumulation are significant contributors. [14]

Specific events

The events that lead to genome instability occur in the cell cycle prior to mitosis, specifically in the S phase. Disturbance to this phase can generate negative effects, such as inaccurate chromosomal segregation, for the upcoming mitotic phase. [10] The two processes that are responsible for damage to the S phase are oncogenic activation and tumor suppressor inactivation. They have both been shown to speed up the transition from the G1 phase to the S phase, leading to inadequate amounts of DNA replication components. These losses can contribute to the DNA damage response (DDR). Replication stress can be an indicative characteristic for carcinogenesis, which typically lacks DNA repair systems. [15] [16] A physiologically short duration of the G1 phase is also typical of fast replicating progenitors during early embryonic development. [17]

Applications in cancer

Rationale for enhancing replication stress to kill cancer cells Rationale for enhancing replication stress to kill cancer cells.png
Rationale for enhancing replication stress to kill cancer cells
Illustration of various approaches to target replication stress for cancer treatment Illustration of various approaches to target replication stress for cancer treatment.png
Illustration of various approaches to target replication stress for cancer treatment

Normal replication stress occurs at low to mild levels and induces genomic instability, which can lead to tumorigenesis and cancer progression. [18] However, high levels of replication stress have been shown to kill cancer cells.

In one study, researchers sought to determine the effects of inducing high levels of replication stress on cancer cells. The results showed that with further loss of checkpoints, replication stress is increased to a higher level. With this change, the DNA replication of cancer cells may be incomplete or incorrect when entering into the mitotic phase, which can eventually result in cell death through mitotic catastrophe. [15]

Another study examined how replication stress affected APOBEC3B activity. APOBEC3 (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3) has been seen to mutate the cancer genome in various cancer types. Results from this study show that weakening oncogenic signaling or intensifying DNA replication stress can alter carcinogenic potential, and can be manipulated therapeutically. [19]

Related Research Articles

Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">DNA replication</span> Biological process

In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part of biological inheritance. This is essential for cell division during growth and repair of damaged tissues, while it also ensures that each of the new cells receives its own copy of the DNA. The cell possesses the distinctive property of division, which makes replication of DNA essential.

<span class="mw-page-title-main">Cell division</span> Process by which living cells divide

Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there are two distinct types of cell division: a vegetative division (mitosis), producing daughter cells genetically identical to the parent cell, and a cell division that produces haploid gametes for sexual reproduction (meiosis), reducing the number of chromosomes from two of each type in the diploid parent cell to one of each type in the daughter cells. Mitosis is a part of the cell cycle, in which, replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis is preceded by the S stage of interphase and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the M phase of an animal cell cycle—the division of the mother cell into two genetically identical daughter cells. To ensure proper progression through the cell cycle, DNA damage is detected and repaired at various checkpoints throughout the cycle. These checkpoints can halt progression through the cell cycle by inhibiting certain cyclin-CDK complexes. Meiosis undergoes two divisions resulting in four haploid daughter cells. Homologous chromosomes are separated in the first division of meiosis, such that each daughter cell has one copy of each chromosome. These chromosomes have already been replicated and have two sister chromatids which are then separated during the second division of meiosis. Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.

<span class="mw-page-title-main">Prophase</span> First phase of cell division in both mitosis and meiosis

Prophase is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the cell enters prophase. The main occurrences in prophase are the condensation of the chromatin reticulum and the disappearance of the nucleolus.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">S phase</span> DNA replication phase of the cell cycle, between G1 and G2 phase

S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

<span class="mw-page-title-main">Homologous recombination</span> Genetic recombination between identical or highly similar strands of genetic material

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.

<span class="mw-page-title-main">Replisome</span> Molecular complex

The replisome is a complex molecular machine that carries out replication of DNA. The replisome first unwinds double stranded DNA into two single strands. For each of the resulting single strands, a new complementary sequence of DNA is synthesized. The total result is formation of two new double stranded DNA sequences that are exact copies of the original double stranded DNA sequence.

<span class="mw-page-title-main">Ataxia telangiectasia and Rad3 related</span> Protein kinase that detects DNA damage and halts cell division

Serine/threonine-protein kinase ATR, also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1), is an enzyme that, in humans, is encoded by the ATR gene. It is a large kinase of about 301.66 kDa. ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ATR is activated in response to single strand breaks, and works with ATM to ensure genome integrity.

<span class="mw-page-title-main">Eukaryotic DNA replication</span> DNA replication in eukaryotic organisms

Eukaryotic DNA replication is a conserved mechanism that restricts DNA replication to once per cell cycle. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">CHEK1</span> Protein-coding gene in humans

Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle.

<span class="mw-page-title-main">TOPBP1</span> Protein-coding gene in the species Homo sapiens

DNA topoisomerase 2-binding protein 1 (TOPBP1) is a scaffold protein that in humans is encoded by the TOPBP1 gene.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

<span class="mw-page-title-main">DNA re-replication</span> Undesirable occurrence in eukaryotic cells

DNA re-replication is an undesirable and possibly fatal occurrence in eukaryotic cells in which the genome is replicated more than once per cell cycle. Rereplication is believed to lead to genomic instability and has been implicated in the pathologies of a variety of human cancers. To prevent rereplication, eukaryotic cells have evolved multiple, overlapping mechanisms to inhibit chromosomal DNA from being partially or fully rereplicated in a given cell cycle. These control mechanisms rely on cyclin-dependent kinase (CDK) activity. DNA replication control mechanisms cooperate to prevent the relicensing of replication origins and to activate cell cycle and DNA damage checkpoints. DNA rereplication must be strictly regulated to ensure that genomic information is faithfully transmitted through successive generations.

Naturally occurring means the damage happens within the cell as a result of normal metabolic processes, without external factors like UV radiation or cigarette smoke causing the damage.

<span class="mw-page-title-main">FAN1</span> Protein-coding gene in the species Homo sapiens

FANCD2/FANCI-associated nuclease 1 (KIAA1018) is an enzyme that in humans is encoded by the FAN1 gene. It is a structure dependent endonuclease. It is thought to play an important role in the Fanconi Anemia (FA) pathway.

<span class="mw-page-title-main">DNA end resection</span> Biochemical process

DNA end resection, also called 5′–3′ degradation, is a biochemical process where the blunt end of a section of double-stranded DNA (dsDNA) is modified by cutting away some nucleotides from the 5' end to produce a 3' single-stranded sequence. The presence of a section of single-stranded DNA (ssDNA) allows the broken end of the DNA to line up accurately with a matching sequence, so that it can be accurately repaired.

<span class="mw-page-title-main">Jan Karlseder</span> Austrian molecular biologist

Jan Karlseder an Austrian molecular biologist, is the Chief Science Officer and a Senior Vice President at the Salk Institute for Biological Studies. He is also a professor in the Molecular and Cellular Biology Laboratory, the Director of the Paul F. Glenn Center for Biology of Aging Research and the holder of the Donald and Darlene Shiley Chair at the Salk Institute for Biological Studies.

References

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  3. ↑ "Reactome | Activation of ATR in response to replication stress". www.reactome.org. Retrieved 2017-04-09.
  4. 1 2 Allen C, Ashley AK, Hromas R, Nickoloff JA (February 2011). "More forks on the road to replication stress recovery". Journal of Molecular Cell Biology. 3 (1): 4–12. doi:10.1093/jmcb/mjq049. PMC   3030971 . PMID   21278446.
  5. ↑ "Replication Fork, Fork Protection Complex | Learn Science at Scitable". www.nature.com. Retrieved 2017-04-09.
  6. ↑ "Stalled DNA Replication Fork | Learn Science at Scitable". www.nature.com. Retrieved 2017-04-09.
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  8. ↑ Cortez D (June 2019). "Replication-Coupled DNA Repair". Molecular Cell. 74 (5): 866–876. doi:10.1016/j.molcel.2019.04.027. PMC   6557297 . PMID   31173722.
  9. 1 2 Pavani R, Tripathi V, Vrtis KB, Zong D, Chari R, Callen E, Pankajam AV, Zhen G, Matos-Rodrigues G, Yang J, Wu S, Reginato G, Wu W, Cejka P, Walter JC, Nussenzweig A (August 2024). "Structure and repair of replication-coupled DNA breaks". Science. 385 (6710): eado3867. doi:10.1126/science.ado3867. PMID   38900911.
  10. 1 2 "Replication Stress in Mammalian Cells and Its Consequences for Mitosis (PDF Download Available)". ResearchGate. Retrieved 2017-02-11.
  11. ↑ King, David; Li, Xiao Dun; Almeida, Gilberto S.; Kwok, Colin; Gravells, Polly; Harrison, Daniel; Burke, Saoirse; Hallsworth, Albert; Jamin, Yann; George, Sally; Robinson, Simon P.; Lord, Christopher J.; Poon, Evon; Yeomanson, Daniel; Chesler, Louis; Bryant, Helen E. (24 September 2019). "MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma". Oncotarget. 11 (23): 2141–2159. doi: 10.18632/oncotarget.27329 . PMC   7289530 . PMID   32577161.
  12. ↑ Burhans WC, Weinberger M (2007). "DNA replication stress, genome instability and aging". Nucleic Acids Research. 35 (22): 7545–56. doi:10.1093/NAR/GKM1059. PMC   2190710 . PMID   18055498.
  13. ↑ Fragkos M, Naim V (April 2017). "Rescue from replication stress during mitosis". Cell Cycle. 16 (7): 613–633. doi:10.1080/15384101.2017.1288322. PMC   5397263 . PMID   28166452.
  14. ↑ Brambati A, Colosio A, Zardoni L, Galanti L, Liberi G (2015-04-28). "Replication and transcription on a collision course: eukaryotic regulation mechanisms and implications for DNA stability". Frontiers in Genetics. 6: 166. doi: 10.3389/fgene.2015.00166 . PMC   4412130 . PMID   25972894.
  15. 1 2 Zhang J, Dai Q, Park D, Deng X (August 2016). "Targeting DNA Replication Stress for Cancer Therapy". Genes. 7 (8): 51. doi: 10.3390/genes7080051 . PMC   4999839 . PMID   27548226.
  16. ↑ Cescon DW, Haibe-Kains B (September 2016). "DNA replication stress: a source of APOBEC3B expression in breast cancer". Genome Biology. 17 (1): 202. doi: 10.1186/s13059-016-1069-y . PMC   5045630 . PMID   27716362.
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  18. ↑ Taylor EM, Lindsay HD (January 2016). "DNA replication stress and cancer: cause or cure?" (PDF). Future Oncology. 12 (2): 221–37. doi:10.2217/fon.15.292. PMID   26616915. S2CID   20261656.
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