The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis.

The accurate repair of DNA double-strand breaks (DSBs), highly toxic DNA lesions, is crucial for genome integrity and is tightly regulated during the cell cycle. In mitosis, cells inactivate DSB repair in favor of a tethering mechanism that stabilizes broken chromosomes until they are repaired in the subsequent cell cycle phases. How this is achieved mechanistically is not yet understood, but the adaptor protein TOPBP1 is critically implicated in this process.

The CIP2A-TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer.

BRCA1/2-mutated cancer cells adapt to the genome instability caused by their deficiency in homologous recombination (HR). Identification of these adaptive mechanisms may provide therapeutic strategies to target tumors caused by the loss of these genes. In the present study, we report genome-scale CRISPR-Cas9 synthetic lethality screens in isogenic pairs of BRCA1- and BRCA2-deficient cells and identify CIP2A as an essential gene in BRCA1- and BRCA2-mutated cells.

Identifying classes of the pain, fatigue, and depression symptom cluster in long-term prostate cancer survivors-results from the multi-regional Prostate Cancer Survivorship Study in Switzerland (PROCAS).

Purpose: Aside from urological and sexual problems, long-term (≥5 years after initial diagnosis) prostate cancer (PC) survivors might suffer from pain, fatigue, and depression. These concurrent symptoms can form a cluster. In this study, we aimed to investigate classes of this symptom cluster in long-term PC survivors, to classify PC survivors accordingly, and to explore associations between classes of this cluster and health-related quality of life (HRQoL).

A Genetic Map of the Response to DNA Damage in Human Cells.

The response to DNA damage is critical for cellular homeostasis, tumor suppression, immunity, and gametogenesis. In order to provide an unbiased and global view of the DNA damage response in human cells, we undertook 31 CRISPR-Cas9 screens against 27 genotoxic agents in the retinal pigment epithelium-1 (RPE1) cell line. These screens identified 890 genes whose loss causes either sensitivity or resistance to DNA-damaging agents.

Health-related quality of life in long-term prostate cancer survivors after nerve-sparing and non-nerve-sparing radical prostatectomy-Results from the multiregional PROCAS study.

Background: Nerve-sparing (NS) surgery was developed to improve postoperative sexual and potentially urological outcomes after radical prostatectomy (RP). However, it is largely unknown how NSRP affects health-related quality of life (HRQoL) including urinary and sexual outcomes in prostate cancer (PC) survivors 5-10 years after diagnosis in comparison with Non-NSRP.

Methods: The study population included 382 stage pT2-T3N0M0 PC survivors 5-10 years post diagnosis, who were identified from the multiregional Prostate Cancer Survivorship in Switzerland (PROCAS) study.

Endogenous DNA 3' Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease.

The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making APE2 a prime target for homologous recombination-defective cancers. However, because the function of APE2 in DNA repair is poorly understood, it is unclear why BRCA-deficient cells require APE2 for viability.

Age-specific health-related quality of life in disease-free long-term prostate cancer survivors versus male population controls-results from a population-based study.

Background: Prostate cancer (PC) and its treatment may affect PC survivors differently with respect to age. However, little is known regarding age-specific health-related quality of life (HRQoL) in PC survivors 5 years or even ≥ 10 years post-diagnosis.

Methods: The sample included 1975 disease-free PC survivors (5-16 years post-diagnosis) and 661 cancer-free population controls, recruited from two German population-based studies (CAESAR+, LinDe).

Control of homologous recombination by the HROB-MCM8-MCM9 pathway.

DNA repair by homologous recombination (HR) is essential for genomic integrity, tumor suppression, and the formation of gametes. HR uses DNA synthesis to repair lesions such as DNA double-strand breaks and stalled DNA replication forks, but despite having a good understanding of the steps leading to homology search and strand invasion, we know much less of the mechanisms that establish recombination-associated DNA polymerization. Here, we report that C17orf53/HROB is an OB-fold-containing factor involved in HR that acts by recruiting the MCM8-MCM9 helicase to sites of DNA damage to promote DNA synthesis.

Health-related quality of life in long-term survivors with localised prostate cancer by therapy-Results from a population-based study.

Objective: Several therapies for localised prostate cancer (PC) are available; all yield similar survival rates. However, each therapy has significant side effects that can influence patients' health-related quality of life (HRQoL) in the long run.

Methods: The study sample included 911 survivors with localised PC, 5-15 years post-diagnosis who were identified from the population-based CAESAR + study in Germany.

The association of cancer-related fatigue with all-cause mortality of colorectal and endometrial cancer survivors: Results from the population-based PROFILES registry.

Purpose: Cancer-related fatigue (CRF) is one of the most prevalent symptoms experienced by cancer survivors. However, researchers are only beginning to elucidate the risk factors, underlying mechanism(s), and its association with other outcomes. Research on the association between CRF and mortality is limited.

BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.

BRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments. Loss of 53BP1 rescues the HR defect in BRCA1-deficient cells by increasing resection, suggesting that BRCA1's downstream role in RAD51 loading is dispensable when 53BP1 is absent.

The Histone Chaperone FACT Coordinates H2A.X-Dependent Signaling and Repair of DNA Damage.

Safeguarding cell function and identity following a genotoxic stress challenge entails a tight coordination of DNA damage signaling and repair with chromatin maintenance. How this coordination is achieved and with what impact on chromatin integrity remains elusive. Here, we address these questions by investigating the mechanisms governing the distribution in mammalian chromatin of the histone variant H2A.

Correction to: Health-related quality of life among long-term (≥5 years) prostate cancer survivors by primary intervention: a systematic review.

The original article [1] contains errors whereby some information provided in Tables 2 and 5 in the online version is missing in the PDF version; in addition, some details regarding the study by Mols et al., Johnstone et al. and Fransson et al.

The shieldin complex mediates 53BP1-dependent DNA repair.

53BP1 is a chromatin-binding protein that regulates the repair of DNA double-strand breaks by suppressing the nucleolytic resection of DNA termini. This function of 53BP1 requires interactions with PTIP and RIF1, the latter of which recruits REV7 (also known as MAD2L2) to break sites. How 53BP1-pathway proteins shield DNA ends is currently unknown, but there are two models that provide the best potential explanation of their action.

Health-related quality of life among long-term (≥5 years) prostate cancer survivors by primary intervention: a systematic review.

Background: Due to an improving prognosis, and increased knowledge of intervention effects over time, long-term well-being among prostate cancer (PC) survivors has gained increasing attention. Yet, despite a variety of available PC interventions, experts currently disagree on optimal intervention course based on survival rates.

Methods: In January 2017, we searched multiple databases to identify relevant articles.

Real-Time Tracking of Parental Histones Reveals Their Contribution to Chromatin Integrity Following DNA Damage.

Chromatin integrity is critical for cell function and identity but is challenged by DNA damage. To understand how chromatin architecture and the information that it conveys are preserved or altered following genotoxic stress, we established a system for real-time tracking of parental histones, which characterize the pre-damage chromatin state. Focusing on histone H3 dynamics after local UVC irradiation in human cells, we demonstrate that parental histones rapidly redistribute around damaged regions by a dual mechanism combining chromatin opening and histone mobilization on chromatin.

Chromatin plasticity in response to DNA damage: The shape of things to come.

DNA damage poses a major threat to cell function and viability by compromising both genome and epigenome integrity. The DNA damage response indeed operates in the context of chromatin and relies on dynamic changes in chromatin organization. Here, we review the molecular bases of chromatin alterations in response to DNA damage, focusing on core histone mobilization in mammalian cells.

Imaging local deposition of newly synthesized histones in UVC-damaged chromatin.

DNA damage not only jeopardizes genome integrity but also challenges the well-organized association of DNA with histone proteins into chromatin, which is key for regulating gene expression and cell functions. The extent to which the original chromatin structure is altered after repair of DNA lesions is thus a critical issue. Dissecting histone dynamics at sites of DNA damage has provided mechanistic insights into chromatin plasticity in response to genotoxic stress.

Blurring the line between the DNA damage response and transcription: the importance of chromatin dynamics.

DNA damage interferes with the progression of transcription machineries. A tight coordination of transcription with signaling and repair of DNA damage is thus critical for safeguarding genome function. This coordination involves modulations of chromatin organization.

How to restore chromatin structure and function in response to DNA damage--let the chaperones play: delivered on 9 July 2013 at the 38th FEBS Congress in St Petersburg, Russia.

Histone deposition onto DNA assisted by specific chaperones forms the chromatin basic unit and serves to package the genome within the cell nucleus. The resulting chromatin organization, often referred to as the epigenome, contributes to a unique transcriptional program that defines cell identity. Importantly, during cellular life, substantial alterations in chromatin structure may arise due to cell stress, including DNA damage, which not only challenges the integrity of the genome but also threatens the epigenome.

Transcription recovery after DNA damage requires chromatin priming by the H3.3 histone chaperone HIRA.

Understanding how to recover fully functional and transcriptionally active chromatin when its integrity has been challenged by genotoxic stress is a critical issue. Here, by investigating how chromatin dynamics regulate transcriptional activity in response to DNA damage in human cells, we identify a pathway involving the histone chaperone histone regulator A (HIRA) to promote transcription restart after UVC damage. Our mechanistic studies reveal that HIRA accumulates at sites of UVC irradiation upon detection of DNA damage prior to repair and deposits newly synthesized H3.

Chromatin dynamics during nucleotide excision repair: histones on the move.

It has been a long-standing question how DNA damage repair proceeds in a nuclear environment where DNA is packaged into chromatin. Several decades of analysis combining in vitro and in vivo studies in various model organisms ranging from yeast to human have markedly increased our understanding of the mechanisms underlying chromatin disorganization upon damage detection and re-assembly after repair. Here, we review the methods that have been developed over the years to delineate chromatin alterations in response to DNA damage by focusing on the well-characterized Nucleotide Excision Repair (NER) pathway.

CTNNBL1 is a novel nuclear localization sequence-binding protein that recognizes RNA-splicing factors CDC5L and Prp31.

Nuclear proteins typically contain short stretches of basic amino acids (nuclear localization sequences; NLSs) that bind karyopherin α family members, directing nuclear import. Here, we identify CTNNBL1 (catenin-β-like 1), an armadillo motif-containing nuclear protein that exhibits no detectable primary sequence homology to karyopherin α, as a novel, selective NLS-binding protein. CTNNBL1 (a single-copy gene conserved from fission yeast to man) was previously found associated with Prp19-containing RNA-splicing complexes as well as with the antibody-diversifying enzyme AID.