Truy tìm dấu vết của XPD: vấn đề chu kỳ tế bào - làm rõ mối quan hệ kiểu gen - kiểu hình của các đột biến XPD

Springer Science and Business Media LLC - Tập 5 - Trang 1-19 - 2010
Elisabetta Cameroni1, Karin Stettler1, Beat Suter1
1Institute of Cell Biology, University of Bern, Bern, Switzerland

Tóm tắt

Các đột biến trong gen người mã hóa cho XPD dẫn đến tình trạng lão hóa từng phần - sự xuất hiện sớm của một số kiểu hình thường liên quan đến tuổi tác - mà có thể đi kèm hoặc không với sự gia tăng tần suất ung thư. XPD là cần thiết cho ít nhất ba chức năng tế bào quan trọng khác nhau: ngoài việc tham gia vào quá trình sửa chữa DNA bằng cách cắt bỏ nucleotide (NER), vốn loại bỏ các tổn thương DNA khối lớn, XPD còn điều chỉnh quá trình sao chép như một phần của yếu tố sao chép chung IIH (TFIIH) và kiểm soát tiến trình chu kỳ tế bào thông qua sự tương tác với CAK, một kích hoạt viên quan trọng của các kinase phụ thuộc cyclin (CDKs). Nghiên cứu các rối loạn di truyền XPD cung cấp cơ hội để hiểu biết thêm về sự phối hợp của các sự kiện tế bào quan trọng và có thể làm sáng tỏ các cơ chế điều chỉnh cân bằng mong manh giữa sự tăng trưởng tế bào và sự lão hóa chức năng, vốn đặc biệt bị thay đổi trong quá trình lão hóa sinh lý và trong ung thư. Những biến thể kiểu hình trong các rối loạn XPD khác nhau là tổng hợp của các rối loạn trong các quá trình sống còn được thực hiện bởi TFIIH và CAK. Ngoài ra, thêm vào các hoạt động tế bào độc lập với TFIIH và CAK của XPD cũng có thể đóng một vai trò. Điều này, cùng với các mạng lưới phản hồi phức tạp hiện diện nhằm đảm bảo sự phối hợp giữa chu kỳ tế bào, sửa chữa DNA và sao chép, làm phức tạp thêm việc giải thích các quan sát lâm sàng. Trong khi các kết quả thu được từ việc cô lập tế bào bệnh nhân cũng như từ các mô hình chuột đã là những yếu tố cơ bản trong việc tiết lộ sự phức tạp như vậy, phôi Drosophila đã chứng tỏ là hữu ích để phân tích vai trò của XPD như một bộ điều chỉnh chu kỳ tế bào độc lập với các chức năng tế bào khác của nó. Cùng với dữ liệu từ phân tích sinh hóa và cấu trúc của XPD và phức hợp TFIIH, các kết quả này kết hợp lại thành một bức tranh mới về các hoạt động của XPD, cung cấp cơ sở cho việc hiểu rõ hơn về bệnh lý học của các bệnh XPD và cho sự phát triển trong tương lai của các công cụ chẩn đoán và điều trị.

Từ khóa

#XPD #chu kỳ tế bào #lão hóa #ung thư #sửa chữa DNA #di truyền học

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