Distinct Motifs in ATAD5 C-Terminal Domain Modulate PCNA Unloading Process.

Proliferating cell nuclear antigen (PCNA) is a DNA clamp that functions in key roles for DNA replication and repair. After the completion of DNA synthesis, PCNA should be unloaded from DNA in a timely way. The ATAD5-RFC-Like Complex (ATAD5-RLC) unloads PCNA from DNA. However, the mechanism of the PCNA-unloading process remains unclear. In this study, we determined the minimal PCNA-unloading domain (ULD) of ATAD5. We identified several motifs in the ATAD5 ULD that are essential in the PCNA-unloading process. The C-terminus of ULD is required for the stable association of RFC2-5 for active RLC formation. The N-terminus of ULD participates in the opening of the PCNA ring. ATAD5-RLC was more robustly bound to open-liable PCNA compared to the wild type. These results suggest that distinct motifs of the ATAD5 ULD participate in each step of the PCNA-unloading process.

Precision targeting tumor cells using cancer-specific InDel mutations with CRISPR-Cas9.

An ideal cancer therapeutic strategy involves the selective killing of cancer cells without affecting the surrounding normal cells. However, researchers have failed to develop such methods for achieving selective cancer cell death because of shared features between cancerous and normal cells. In this study, we have developed a therapeutic strategy called the cancer-specific insertions-deletions (InDels) attacker (CINDELA) to selectively induce cancer cell death using the CRISPR-Cas system. CINDELA utilizes a previously unexplored idea of introducing CRISPR-mediated DNA double-strand breaks (DSBs) in a cancer-specific fashion to facilitate specific cell death. In particular, CINDELA targets multiple InDels with CRISPR-Cas9 to produce many DNA DSBs that result in cancer-specific cell death. As a proof of concept, we demonstrate here that CINDELA selectively kills human cancer cell lines, xenograft human tumors in mice, patient-derived glioblastoma, and lung patient-driven xenograft tumors without affecting healthy human cells or altering mouse growth.

PM10 and pregnancy outcomes: a hospital-based cohort study of pregnant women in Seoul.

OBJECTIVE: : The aim of this study was to evaluate the effects of PM10 on birth outcomes using a prospective cohort of pregnant women. METHODS: : The multicenter prospective study was conducted in Korea from 2001 to 2004. To estimate the effects of PM10 exposure on birth outcomes, the logistic and linear regression model and the generalized additive model for nonlinear relationships were used. RESULTS: : Stillbirths were affected by PM10 level during the third trimesters (OR = 1.10, 95% CI = 1.02-1.14), and birth defects were influenced by the PM10 exposure during the second trimesters (OR = 1.16, 95% CI = 1.00-1.34). Intrauterine growth retardation was affected by the first trimester's PM10 exposure. On the other hand, premature birth was affected by the PM10 exposure during the third trimester, and low-birth-weight births were affected by the PM10 level during entire trimesters of pregnancy. CONCLUSIONS: : PM10 exposure during pregnancy may result in adverse birth outcomes with different critical periods.